Is GRIN2C p.Pro677Ser (c.2029C>T) pathogenic?

GRIN2C p.Pro677Ser (c.2029C>T) is classified Uncertain significance in GRIN2C (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-19). AlphaMissense: ambiguous (0.4405); Ultra-rare (popmax 0.0516%, sas).

How common is GRIN2C p.Pro677Ser (c.2029C>T) in the general population?

GRIN2C p.Pro677Ser (c.2029C>T) is ultra-rare (popmax 0.0516%, sas) (gnomAD).

What do computational predictors say about GRIN2C p.Pro677Ser (c.2029C>T)?

AlphaMissense predicts ambiguous (score 0.4405) — an in-silico prediction, not a clinical call.

GRIN2C p.Pro677Ser

c.2029C>T · rs369304620 · VCV3102482

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4405 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0516%, sas)

Computational evidence

Protein change
AlphaMissense	0.4405	ambiguous
REVEL	0.294	indeterminate
SaProt	LLR -11.66	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 7,960 bp · p 1.4e-06 · regional, not allelic
Overall
CADD	31.0	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 0.0516% South Asian · 47/91,072 alleles

Filtering AF 0.0399% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0357%

Overall 0.00446% 72/1,613,638 alleles · ultra-rare exomes 61/1,461,384 · genomes 11/152,254 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0516%	1,938
African / African-American	0.0254%	3,944
Remaining individualsnot grpmax-eligible	0.0064%	15,619
East Asian	0.00223%	44,890
Admixed American	0.00167%	59,990

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: GRIN2C
Protein: p.Pro677Ser
Coding: c.2029C>T
MANE Select: NM_000835
dbSNP: rs369304620
Type: single nucleotide variant
Location: chr17:74846893 (GRCh38)
Gene constraint: LOEUF 1.163 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.06 · 6 PDB
Residue 677: a UniProt-annotated variant site (found in a patient with autism spectrum disorder; uncertain significance)

Full GRIN2C gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

GRIN2C p.Ala8Thr Likely benign ★★ same type
GRIN2C p.Ala999= Likely benign ★★ same type
GRIN2C p.Arg401Gln Benign ★★ same type
GRIN2C p.Arg435= Benign ★★ same type
GRIN2C p.Ile519= Benign/Likely benign ★★ same type
GRIN2C p.Leu65Phe Likely benign ★★ same type
GRIN2C p.Thr1196Ile Benign ★★ same type
GRIN2C p.Val191Ala Likely benign ★★ 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/grin2c-p-pro677ser (accessed [today's date]).

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