Is GPR65 p.Ser39Phe (c.116C>T) pathogenic?

GPR65 p.Ser39Phe (c.116C>T) is classified Uncertain significance in GPR65 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-29). AlphaMissense: likely pathogenic (0.8961); Ultra-rare (popmax 0.0267%, afr).

How common is GPR65 p.Ser39Phe (c.116C>T) in the general population?

GPR65 p.Ser39Phe (c.116C>T) is ultra-rare (popmax 0.0267%, afr) (gnomAD).

What do computational predictors say about GPR65 p.Ser39Phe (c.116C>T)?

AlphaMissense predicts likely pathogenic (score 0.8961) — an in-silico prediction, not a clinical call.

GPR65 p.Ser39Phe

c.116C>T · rs139430517 · VCV2321324

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8961 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0267%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8961	likely pathogenic
REVEL	0.234	benign-leaning
SaProt	LLR -6.95	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	GERP 2.8, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 1,010 bp · p 0.31 · regional, not allelic
Overall
CADD	26.0	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 0.0267% African / African-American · 20/74,876 alleles

Filtering AF 0.0177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0147%

Overall 0.00124% 20/1,613,268 alleles · ultra-rare exomes 10/1,461,144 · genomes 10/152,124 · 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: GPR65
Protein: p.Ser39Phe
Coding: c.116C>T
MANE Select: NM_003608
dbSNP: rs139430517
Type: single nucleotide variant
Location: chr14:88010963 (GRCh38)
Gene constraint: LOEUF 1.933 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.53 · 2 PDB
Residue 39: an α-helix

Full GPR65 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

GPR65 p.Ala109Thr Uncertain significance ★ ⚠ same type
GPR65 p.Ala115Gly Uncertain significance ★ same type
GPR65 p.Ala215Val Uncertain significance ★ ⚠ same type
GPR65 p.Arg129Thr Uncertain significance ★ ⚠ same type
GPR65 p.Arg204Trp Uncertain significance ★ ⚠ same type
GPR65 p.Arg319Lys Uncertain significance ★ ⚠ same type
GPR65 p.Asn166Tyr Uncertain significance ★ ⚠ same type
GPR65 p.Cys5Arg 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/gpr65-p-ser39phe (accessed [today's date]).

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