Is GRM2 p.Phe535Ser (c.1604T>C) pathogenic?

GRM2 p.Phe535Ser (c.1604T>C) is classified Uncertain significance in GRM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-15). AlphaMissense: ambiguous (0.4939); Ultra-rare (popmax 0.0717%, amr).

How common is GRM2 p.Phe535Ser (c.1604T>C) in the general population?

GRM2 p.Phe535Ser (c.1604T>C) is ultra-rare (popmax 0.0717%, amr) (gnomAD).

What do computational predictors say about GRM2 p.Phe535Ser (c.1604T>C)?

AlphaMissense predicts ambiguous (score 0.4939) — an in-silico prediction, not a clinical call.

GRM2 p.Phe535Ser

c.1604T>C · VCV4032558

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4939 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0717%, amr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4939	ambiguous
REVEL	0.801	moderately pathogenic-leaning
SaProt	LLR -9.81	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.1	GERP 1.9, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 9,125 bp · p 2.3e-15 · regional, not allelic
Overall
CADD	22.5	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 0.0717% Admixed American · 43/60,012 alleles

Filtering AF 0.0546% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0486%

Overall 0.00273% 44/1,613,588 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0717%	1,396
African / African-American	0.00133%	74,956

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: GRM2
Protein: p.Phe535Ser
Coding: c.1604T>C
MANE Select: NM_000839
Type: single nucleotide variant
Location: chr3:51715377 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.17 · 31 PDB
Residue 535: a disulfide bond

Full GRM2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

GRM2 p.Asn824= Benign ★★ same type
GRM2 p.Ala127Glu Uncertain significance ★ ⚠ same type
GRM2 p.Ala275Val Uncertain significance ★ same type
GRM2 p.Ala281Val Uncertain significance ★ ⚠ same type
GRM2 p.Ala287Val Uncertain significance ★ ⚠ same type
GRM2 p.Ala363Thr Uncertain significance ★ ⚠ same type
GRM2 p.Ala430Val Uncertain significance ★ same type
GRM2 p.Ala47Val 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/grm2-p-phe535ser (accessed [today's date]).

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