Is CYP2C8 p.Pro174Ser (c.520C>T) pathogenic?

CYP2C8 p.Pro174Ser (c.520C>T) is classified Uncertain significance in CYP2C8 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-13). AlphaMissense: likely benign (0.2661); Very rare (popmax 0.00577%, nfe).

How common is CYP2C8 p.Pro174Ser (c.520C>T) in the general population?

CYP2C8 p.Pro174Ser (c.520C>T) is very rare (popmax 0.00577%, nfe) (gnomAD).

What do computational predictors say about CYP2C8 p.Pro174Ser (c.520C>T)?

AlphaMissense predicts likely benign (score 0.2661) — an in-silico prediction, not a clinical call.

CYP2C8 p.Pro174Ser

c.520C>T · rs772144986 · VCV2255325

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2661 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00577%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2661	likely benign
REVEL	0.265	benign-leaning
SaProt	LLR -12.78	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.088	GERP 1
Regional constraint	o/e 1.12	unconstrained · MANE · 32 kb · p 0.0032 · regional, not allelic
Overall
CADD	18.23	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 0.00577% European (non-Finnish) · 68/1,179,152 alleles

Filtering AF 0.00462% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00423%

Overall 0.00428% 69/1,611,244 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00577%	17,340
Remaining individualsnot grpmax-eligible	0.0016%	62,308

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.Pro174Ser
Coding: c.520C>T
MANE Select: NM_000770
dbSNP: rs772144986
Type: single nucleotide variant
Location: chr10:95064922 (GRCh38)
Gene constraint: LOEUF 1.502 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.07 · 5 PDB
Residue 174: 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-pro174ser (accessed [today's date]).

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