Is CYP2C8 p.Val75Met (c.223G>A) pathogenic?

CYP2C8 p.Val75Met (c.223G>A) is classified Uncertain significance in CYP2C8 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-11). AlphaMissense: likely pathogenic (0.6817); Absent from gnomAD v4.1.

How common is CYP2C8 p.Val75Met (c.223G>A) in the general population?

CYP2C8 p.Val75Met (c.223G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CYP2C8 p.Val75Met (c.223G>A)?

AlphaMissense predicts likely pathogenic (score 0.6817) — an in-silico prediction, not a clinical call.

CYP2C8 p.Val75Met

c.223G>A · rs2492789134 · VCV2288719

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6817 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6817	likely pathogenic
REVEL	0.337	indeterminate
SaProt	LLR -11.75	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.006	GERP 1.9, phastCons 0.001
Regional constraint	o/e 1.12	unconstrained · MANE · 32 kb · p 0.0032 · regional, not allelic
Overall
CADD	19.55	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CYP2C8
Protein: p.Val75Met
Coding: c.223G>A
MANE Select: NM_000770
dbSNP: rs2492789134
Type: single nucleotide variant
Location: chr10:95067637 (GRCh38)
Gene constraint: LOEUF 1.502 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.07 · 5 PDB
Residue 75: a β-strand

Full CYP2C8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CYP2C8 c.168+669A>G Benign ★★ same type
CYP2C8 p.His353= Benign ★★ same type
CYP2C8 p.Val181Ile Benign ★★ same type
CYP2C8 p.Ala253Pro Uncertain significance ★ ⚠ same type
CYP2C8 p.Arg200Lys Uncertain significance ★ ⚠ same type
CYP2C8 p.Asn133Asp Uncertain significance ★ ⚠ same type
CYP2C8 p.Asn176Ser Uncertain significance ★ ⚠ same type
CYP2C8 p.Asn176Thr Uncertain significance ★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/cyp2c8-p-val75met (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown