Is CYP2C8 p.Val181Ile (c.541G>A) pathogenic?

CYP2C8 p.Val181Ile (c.541G>A) is classified Benign in CYP2C8 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2018-07-06). AlphaMissense: likely benign (0.0816); Rare (popmax 0.844%, nfe).

How common is CYP2C8 p.Val181Ile (c.541G>A) in the general population?

CYP2C8 p.Val181Ile (c.541G>A) is rare (popmax 0.844%, nfe) (gnomAD).

What do computational predictors say about CYP2C8 p.Val181Ile (c.541G>A)?

AlphaMissense predicts likely benign (score 0.0816) — an in-silico prediction, not a clinical call.

CYP2C8 p.Val181Ile

c.541G>A · rs41286886 · VCV787628

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0816 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.844%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0816	likely benign
REVEL	0.05	moderately benign-leaning
SaProt	LLR -3.20	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -11	GERP -3.4
Regional constraint	o/e 1.12	unconstrained · MANE · 32 kb · p 0.0032 · regional, not allelic
Overall
CADD	1.79	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.844% European (non-Finnish) · 9,959/1,179,922 alleles

Filtering AF 0.83% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.824%

Overall 0.681% 10,994/1,613,260 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.844%	118
Finnishnot grpmax-eligible	0.683%	146
Remaining individualsnot grpmax-eligible	0.484%	207
Admixed American	0.222%	451
African / African-American	0.125%	797
South Asian	0.0659%	1,517
Middle Eastern	0.0353%	2,836
Ashkenazi Jewishnot grpmax-eligible	0.0169%	5,920
East Asian	0.00446%	22,427

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.Val181Ile
Coding: c.541G>A
MANE Select: NM_000770
dbSNP: rs41286886
Type: single nucleotide variant
Location: chr10:95064901 (GRCh38)
Gene constraint: LOEUF 1.502 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.07 · 5 PDB
Residue 181: 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.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
CYP2C8 p.Asn236Tyr 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-val181ile (accessed [today's date]).

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