Is GRIN2D p.Pro291Ser (c.871C>T) pathogenic?

GRIN2D p.Pro291Ser (c.871C>T) is classified Uncertain significance in GRIN2D (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-14). AlphaMissense: likely benign (0.0815); Very rare (popmax 0.00135%, afr); Associated with Inborn genetic diseases.

What condition is associated with GRIN2D p.Pro291Ser (c.871C>T)?

GRIN2D p.Pro291Ser (c.871C>T) is associated with Inborn genetic diseases (ClinVar).

How common is GRIN2D p.Pro291Ser (c.871C>T) in the general population?

GRIN2D p.Pro291Ser (c.871C>T) is very rare (popmax 0.00135%, afr) (gnomAD).

What do computational predictors say about GRIN2D p.Pro291Ser (c.871C>T)?

AlphaMissense predicts likely benign (score 0.0815) — an in-silico prediction, not a clinical call.

GRIN2D p.Pro291Ser

c.871C>T · VCV3855815

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0815 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00135%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0815	likely benign
REVEL	0.147	moderately benign-leaning
SaProt	LLR -7.76	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.1	GERP 0.49, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 16 kb · p 5.9e-06 · regional, not allelic
Overall
CADD	22.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00135% African / African-American · 1/74,108 alleles

Overall 0.000127% 2/1,573,466 alleles · very rare exomes 2/1,421,130 · genomes 0/152,336 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00135%	74,108
European (non-Finnish)	8.62e-05%	1,160,658

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: GRIN2D
Protein: p.Pro291Ser
Coding: c.871C>T
MANE Select: NM_000836
Type: single nucleotide variant
Location: chr19:48405139 (GRCh38)
Gene constraint: LOEUF 0.642 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 64.00 · 13 PDB

Full GRIN2D gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

GRIN2D p.Pro291Thr Uncertain significance ★★ ⚠ same residue
GRIN2D p.Pro291Arg Uncertain significance ★ ⚠ same residue
GRIN2D p.Pro291= Likely benign ★ same residue
GRIN2D p.Ala1032Val Uncertain significance ★★ ⚠ same condition
GRIN2D p.Ala1135Thr Uncertain significance ★★ ⚠ same condition
GRIN2D p.Ala1208Val Uncertain significance ★★ ⚠ same condition
GRIN2D p.Ala1244Val Uncertain significance ★★ ⚠ same condition
GRIN2D p.Ala1256Thr Uncertain significance ★★ ⚠ same condition

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/grin2d-p-pro291ser (accessed [today's date]).

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