Is GPR4 p.Leu272Pro (c.815T>C) pathogenic?

GPR4 p.Leu272Pro (c.815T>C) is classified Uncertain significance in GPR4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-18). AlphaMissense: likely pathogenic (0.996); Absent from gnomAD v4.1.

How common is GPR4 p.Leu272Pro (c.815T>C) in the general population?

GPR4 p.Leu272Pro (c.815T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about GPR4 p.Leu272Pro (c.815T>C)?

AlphaMissense predicts likely pathogenic (score 0.996) — an in-silico prediction, not a clinical call.

GPR4 p.Leu272Pro

c.815T>C · VCV3855347

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.996 · 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	0.996	likely pathogenic · top 3% in GPR4
REVEL	0.516	indeterminate
SaProt	LLR -15.96	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 9.4	GERP 2, phastCons 1
Regional constraint	o/e 0.06	constrained · MANE · 39 bp · p 0.00016 · regional, not allelic
Overall
CADD	27.6	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: GPR4
Protein: p.Leu272Pro
Coding: c.815T>C
MANE Select: NM_005282
Type: single nucleotide variant
Location: chr19:45591052 (GRCh38)
Gene constraint: LOEUF 0.92 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.97 · 25 PDB
Residue 272: 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-leu272pro (accessed [today's date]).

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