Is GPR6 p.Ser53Phe (c.158C>T) pathogenic?

GPR6 p.Ser53Phe (c.158C>T) is classified Uncertain significance in GPR6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-21). AlphaMissense: likely pathogenic (0.7112); Very rare (popmax 0.00669%, eas).

How common is GPR6 p.Ser53Phe (c.158C>T) in the general population?

GPR6 p.Ser53Phe (c.158C>T) is very rare (popmax 0.00669%, eas) (gnomAD).

What do computational predictors say about GPR6 p.Ser53Phe (c.158C>T)?

AlphaMissense predicts likely pathogenic (score 0.7112) — an in-silico prediction, not a clinical call.

GPR6 p.Ser53Phe

c.158C>T · rs764417293 · VCV3101800

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7112 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00669%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.7112	likely pathogenic
REVEL	0.333	indeterminate
SaProt	LLR -11.84	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 1,085 bp · p 0.4 · regional, not allelic
Overall
CADD	24.5	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 0.00669% East Asian · 3/44,862 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000892%

Overall 0.000186% 3/1,612,720 alleles · very rare exomes 2/1,460,556 · genomes 1/152,164 · joint denominator

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: GPR6
Protein: p.Ser53Phe
Coding: c.158C>T
MANE Select: NM_005284
dbSNP: rs764417293
Type: single nucleotide variant
Location: chr6:109979270 (GRCh38)
Gene constraint: LOEUF 1.137 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.92 · 4 PDB

Full GPR6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

GPR6 p.Ala121Glu Uncertain significance ★ ⚠ same type
GPR6 p.Ala153Ser Uncertain significance ★ ⚠ same type
GPR6 p.Ala173Ser Uncertain significance ★ ⚠ same type
GPR6 p.Ala214Ser Uncertain significance ★ ⚠ same type
GPR6 p.Ala232Thr Uncertain significance ★ ⚠ same type
GPR6 p.Ala260Thr Uncertain significance ★ ⚠ same type
GPR6 p.Ala273Val Uncertain significance ★ ⚠ same type
GPR6 p.Ala308Thr 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/gpr6-p-ser53phe (accessed [today's date]).

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