Is GRIN2D p.Arg1012Pro (c.3035G>C) pathogenic?

GRIN2D p.Arg1012Pro (c.3035G>C) is classified Uncertain significance in GRIN2D (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-10). AlphaMissense: ambiguous (0.5576); Very rare (popmax 0.00375%, amr); Associated with Inborn genetic diseases.

What condition is associated with GRIN2D p.Arg1012Pro (c.3035G>C)?

GRIN2D p.Arg1012Pro (c.3035G>C) is associated with Inborn genetic diseases (ClinVar).

How common is GRIN2D p.Arg1012Pro (c.3035G>C) in the general population?

GRIN2D p.Arg1012Pro (c.3035G>C) is very rare (popmax 0.00375%, amr) (gnomAD).

What do computational predictors say about GRIN2D p.Arg1012Pro (c.3035G>C)?

AlphaMissense predicts ambiguous (score 0.5576) — an in-silico prediction, not a clinical call.

GRIN2D p.Arg1012Pro

c.3035G>C · rs1447126523 · VCV1319387

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.5576 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00375%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5576	ambiguous
REVEL	0.115	moderately benign-leaning
SaProt	LLR -7.66	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.1	GERP 0.55, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 1,409 bp · p 0.013 · regional, not allelic
Overall
CADD	24.2	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 0.00375% Admixed American · 1/26,644 alleles

Filtering AF 3.6e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.4e-05%

Overall 0.000262% 3/1,142,950 alleles · very rare exomes 2/996,972 · genomes 1/145,978 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00375%	26,644
European (non-Finnish)	0.000217%	460,443

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.Arg1012Pro
Coding: c.3035G>C
MANE Select: NM_000836
dbSNP: rs1447126523
Type: single nucleotide variant
Location: chr19:48442961 (GRCh38)
Gene constraint: LOEUF 0.642 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 64.00 · 13 PDB
Residue 1012: the 'disordered' region

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.Arg1012Cys Uncertain significance ★ ⚠ same residue
GRIN2D p.Arg1012His Uncertain significance ★ ⚠ same residue
GRIN2D p.Arg1012= 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-arg1012pro (accessed [today's date]).

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