OneKGPd-MCP

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real-timeaccess to138 044 723unique variants and~442 billionindividual genotypes

variant, sample and genotype selection based on coordinates, annotations, zygosity, population

filtering by VEP (impact, biotype, feature type, variant class, consequences), ClinVar Clinical Significance (202502), gnomADe + gnomADg 4.1, AlphaMissense Score & AlphaMissense Class annotations

returned variants annotated withHGVSp,gnomADe + gnomADg,AlphaMissense score+ cohort-wide statistics

- HGVSpannotations are forCanonical transcriptsto reduce LLMs cognitive load

samples annotated with:familyId, gender, paternalId, maternalId, relationship, children, population, superpopulation, phase3 indicator

Treat the 26S Proteasome as a mechanically redundant 3D machine and map every missense variant from the KGP individuals across all 33 subunits. Perform a spatial analysis to determine if pathogenic variation is statistically partitioned toward the distal 'Lid' (Zone C) rather than the more evolutionary constrained 'Core' (Zone A) or 'Gating' (Zone B) interfaces. Identify individuals with a high cumulative burden (2+ 'Likely Pathogenic' variants) to investigate inter-subunit compensation, searching for paired 'weakening' and 'stabilizing' mutations at protein-protein hinges. Finally, define the 'mechanical tolerance' of the proteasome by establishing the maximum cumulative structural disruption observed in a single healthy individual based on AlphaMissense scores and calculated ΔΔG values.

The MCM2-7 Complex (The "DNA Helicase Motor") is a molecular masterpiece. It’s a heterohexameric ring where each subunit is a distinct "gear" in the DNA-unzipping motor. Unlike homomeric rings (where every subunit is the same), this complex is asymmetric. Each interface between subunits is unique, and they don't all burn ATP at the same rate. The MCM2/5 interface is the "gate" that must physically open to allow DNA to enter the ring and then snap shut. This is a high-stress mechanical point.

Identify individuals in the KGP cohort carrying missense variants at the MCM2/5 interface. Specifically, look for 'charge-reversal' variants (e.g., Aspartate to Lysine). In these specific samples, analyze the 'compensatory coupling': do they carry a secondary, reciprocal charge-reversal variant on the opposing subunit interface that restores the electrostatic 'latch' ?

Identify individuals in the KGP cohort who carry high-pathogenicity variants in the Walker A or Walker B motifs (the ATP-burning heart) of any MCM subunit in MCM2-7 Complex. For these individuals, perform a 'Systemic Flux' analysis: look at their variants in the leading-strand polymerase (POLE) and the sliding clamp (PCNA). Do you detect a signature of 'Coordinated Deceleration' where the motor, the clamp, and the polymerase all carry variants that suggest a slower but highly-accurate replication fork ?

The human RNA Exosome (Exo-9 core) is a "dead machine" that acts as a scaffold. In lower organisms the ring itself can degrade RNA. In humans, the 9-subunit ring has lost all its catalytic teeth and is purely a structural tunnel that guides RNA into the catalytic subunits (DIS3 or EXOSC10) attached at the bottom. Since RNA is a highly negatively charged polymer, the residues lining this pore are typically positively charged (Lysine, Arginine), but not too "sticky" or RNA will jam. So, to reach the "shredder" at the bottom it must slide through a narrow pore formed by the Exo-9 ring.

The task: analyse all missense variants in the KGP cohort that map to the internal pore-lining residues of the Exo-9 ring. Look for 'charge-swap' variants where a positive residue (K, R) is replaced by a negative one (D, E). If an individual is healthy despite having a 'negative patch' in the tunnel that should repel RNA, do they carry a compensatory variant in the cap subunits (EXOSC1, 2, 3) that widens the entrance? Use a 3D electrostatic surface map to determine if the 'healthy' cohort maintains a specific electrostatic gradient.

Synergistic Epistasis in Redox Homeostasis

Cellular redox homeostasis is maintained by two parallel antioxidant systems: the glutathione system and the thioredoxin system. Complete loss of either GSR or TXNRD1 is incompatible with mammalian development, yet population databases contain individuals carrying variants predicted to impair enzyme function.

Identify clusters of individuals in the KGP cohort who carry multiple 'Moderate' impact VEP variants across both systems. Reasoning through the AlphaMissense structural implications, can you detect a 'balancing act' where a loss of efficiency in Glutathione reductase is consistently paired with high-confidence benign or potentially activating variants in the Thioredoxin system ? Synthesize a model of 'Redox Robustness' based on the co-occurrence of these variants across the cohort.

Implemented as a Java EE service, accessingKGP datasetvia gRPC calls to public Dnaerys variant store service.

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provides MCP overStreamable HTTP,HTTP/SSEandSTDIOtransports

sample population and metadata are managed by an embedded DuckDB instance

Project can be run locally with MCP overstdioand/orhttptransports

- build the project and package it as a singleüber-jar:

- jar is located intarget/onekgpd-mcp-runner.jarand includes all dependencies

./mvnw clean package -DskipTests -Dquarkus.package.jar.type=uber-jar

./mvnw clean package -Dmaven.test.skip=true -Dquarkus.package.jar.type=uber-jar

- run it locally withdev profile

java -Dquarkus.profile=dev -jar <full path>/onekgpd-mcp-runner.jar

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to connect viahttptransport,remote or local, simply direct the client to a destination,e.g.http://localhost:9000/mcporhttps://db.dnaerys.org:443/mcp

- NB:Claude Desktopwon't work withhttp://localhost:9000/mcpoption. This option is for clients likeGoose.

to connect viastdiotransport, MCP client should start application withdev profileand with a full path to the jar file

- e.g. forClaude Desktopadd to config files (e.g.claude_desktop_config.json):

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