Is GPR139 p.Arg57Ser (c.171A>C) pathogenic?

GPR139 p.Arg57Ser (c.171A>C) is classified Uncertain significance in GPR139 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-24). AlphaMissense: likely pathogenic (0.8043); Ultra-rare (popmax 0.0402%, eas).

How common is GPR139 p.Arg57Ser (c.171A>C) in the general population?

GPR139 p.Arg57Ser (c.171A>C) is ultra-rare (popmax 0.0402%, eas) (gnomAD).

What do computational predictors say about GPR139 p.Arg57Ser (c.171A>C)?

AlphaMissense predicts likely pathogenic (score 0.8043) — an in-silico prediction, not a clinical call.

GPR139 p.Arg57Ser

c.171A>C · VCV4265729

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8043 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0402%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8043	likely pathogenic
REVEL	0.39	indeterminate
SaProt	LLR -5.25	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.61	GERP -3.7, phastCons 0.026
Regional constraint	o/e 0.84	unconstrained · MANE · 42 kb · p 0.00094 · regional, not allelic
Overall
CADD	21.5	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 0.0402% East Asian · 18/44,772 alleles

Filtering AF 0.0259% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0214%

Overall 0.00118% 19/1,610,744 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0402%	2,487
European (non-Finnish)	8.5e-05%	1,177,152

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: GPR139
Protein: p.Arg57Ser
Coding: c.171A>C
MANE Select: NM_001002911
Type: single nucleotide variant
Location: chr16:20032626 (GRCh38)
Gene constraint: LOEUF 0.728 · pLI 0.11 (gnomAD)
Structure: AlphaFold pLDDT 77.89 · 5 PDB
Residue 57: an α-helix

Full GPR139 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

GPR139 p.Ala242Thr Uncertain significance ★ ⚠ same type
GPR139 p.Ala330Val Uncertain significance ★ same type
GPR139 p.Arg144Cys Uncertain significance ★ ⚠ same type
GPR139 p.Arg144His Uncertain significance ★ same type
GPR139 p.Arg212Met Uncertain significance ★ ⚠ same type
GPR139 p.Arg291Gln Uncertain significance ★ ⚠ same type
GPR139 p.Arg291Pro Uncertain significance ★ ⚠ same type
GPR139 p.Asp89Glu 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/gpr139-p-arg57ser (accessed [today's date]).

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