Is CYP2C8 p.Pro30Thr (c.88C>A) pathogenic?

CYP2C8 p.Pro30Thr (c.88C>A) is classified Uncertain significance in CYP2C8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-16). AlphaMissense: likely pathogenic (0.8506); Ultra-rare (popmax 0.0133%, afr).

How common is CYP2C8 p.Pro30Thr (c.88C>A) in the general population?

CYP2C8 p.Pro30Thr (c.88C>A) is ultra-rare (popmax 0.0133%, afr) (gnomAD).

What do computational predictors say about CYP2C8 p.Pro30Thr (c.88C>A)?

AlphaMissense predicts likely pathogenic (score 0.8506) — an in-silico prediction, not a clinical call.

CYP2C8 p.Pro30Thr

c.88C>A · VCV4008835

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8506 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8506	likely pathogenic
REVEL	0.716	pathogenic-leaning
SaProt	LLR -14.97	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.2	GERP 1.9, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 32 kb · p 0.0032 · regional, not allelic
Overall
CADD	22.5	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

Grpmax group 0.0133% African / African-American · 10/74,914 alleles

Filtering AF 0.00723% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0055%

Overall 0.000744% 12/1,613,922 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0133%	7,491
Remaining individualsnot grpmax-eligible	0.0032%	31,237

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: CYP2C8
Protein: p.Pro30Thr
Coding: c.88C>A
MANE Select: NM_000770
Type: single nucleotide variant
Location: chr10:95069315 (GRCh38)
Gene constraint: LOEUF 1.502 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.07 · 5 PDB
Residue 30: an α-helix

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-pro30thr (accessed [today's date]).

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