Is GPR4 p.Phe265Cys (c.794T>G) pathogenic?

GPR4 p.Phe265Cys (c.794T>G) is classified Uncertain significance in GPR4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-28). AlphaMissense: likely pathogenic (0.9866); Very rare (popmax 0.00167%, amr).

How common is GPR4 p.Phe265Cys (c.794T>G) in the general population?

GPR4 p.Phe265Cys (c.794T>G) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about GPR4 p.Phe265Cys (c.794T>G)?

AlphaMissense predicts likely pathogenic (score 0.9866) — an in-silico prediction, not a clinical call.

GPR4 p.Phe265Cys

c.794T>G · rs1568415993 · VCV3101772

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9866 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9866	likely pathogenic · top 9% in GPR4
REVEL	0.535	indeterminate
SaProt	LLR -10.41	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 8.1	GERP 2, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 805 bp · p 1.3e-07 · regional, not allelic
Overall
CADD	24.9	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 0.00167% Admixed American · 1/60,010 alleles

Overall 0.000657% 1/152,252 alleles · very rare

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: GPR4
Protein: p.Phe265Cys
Coding: c.794T>G
MANE Select: NM_005282
dbSNP: rs1568415993
Type: single nucleotide variant
Location: chr19:45591073 (GRCh38)
Gene constraint: LOEUF 0.92 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.97 · 25 PDB
Residue 265: an α-helix

Full GPR4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

GPR4 p.Ala195Thr Uncertain significance ★ ⚠ same type
GPR4 p.Ala195Val Uncertain significance ★ ⚠ same type
GPR4 p.Ala231Val Uncertain significance ★ ⚠ same type
GPR4 p.Ala293Thr Uncertain significance ★ ⚠ same type
GPR4 p.Arg216Leu Uncertain significance ★ ⚠ same type
GPR4 p.Arg254His Uncertain significance ★ ⚠ same type
GPR4 p.Arg263Cys Uncertain significance ★ ⚠ same type
GPR4 p.Arg306Cys 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/gpr4-p-phe265cys (accessed [today's date]).

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