Is GRIN2D p.Ala955fs (c.2861dup) pathogenic?

GRIN2D p.Ala955fs (c.2861dup) is classified Uncertain significance in GRIN2D (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-25). Ultra-rare (popmax 0.0231%, sas).

How common is GRIN2D p.Ala955fs (c.2861dup) in the general population?

GRIN2D p.Ala955fs (c.2861dup) is ultra-rare (popmax 0.0231%, sas) (gnomAD).

GRIN2D p.Ala955fs

c.2861dup · rs1569074871 · VCV1998696

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0231%, sas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (14 of 14) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 2	GERP 1, phastCons 0.039
Overall
CADD	25.3	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0231% South Asian · 6/25,942 alleles

Filtering AF 0.0101% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00682%

Overall 0.0014% 15/1,068,170 alleles · ultra-rare exomes 15/920,994 · genomes 0/147,176 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0231%	4,324
East Asian	0.00699%	14,312
European (non-Finnish)	0.000904%	110,638

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.Ala955fs
Coding: c.2861dup
MANE Select: NM_000836
dbSNP: rs1569074871
Type: Duplication
Location: chr19:48442781 (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

Similar variants

GRIN2D p.Ala955= Likely benign ★ same residue
GRIN2D p.1076AGG[3] Uncertain significance ★ same type
GRIN2D p.Arg1225fs Uncertain significance ★ same type
GRIN2D p.Arg421fs Uncertain significance ★ same type
GRIN2D p.Arg651fs Uncertain significance ★ same type
GRIN2D p.Glu65_Ala72dup Conflicting classifications of pathogenicity ★ same type
GRIN2D p.Gly1258fs Uncertain significance ★ same type
GRIN2D p.Gly303fs 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/grin2d-p-ala955fs (accessed [today's date]).

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