Is GRID2 p.Pro678Ala (c.2032C>G) pathogenic?

GRID2 p.Pro678Ala (c.2032C>G) is classified Conflicting classifications of pathogenicity in GRID2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2024-11-22). AlphaMissense: likely benign (0.0885); Rare (popmax 0.264%, afr); Associated with Inborn genetic diseases.

What condition is associated with GRID2 p.Pro678Ala (c.2032C>G)?

GRID2 p.Pro678Ala (c.2032C>G) is associated with Inborn genetic diseases (ClinVar).

How common is GRID2 p.Pro678Ala (c.2032C>G) in the general population?

GRID2 p.Pro678Ala (c.2032C>G) is rare (popmax 0.264%, afr) (gnomAD).

What do computational predictors say about GRID2 p.Pro678Ala (c.2032C>G)?

AlphaMissense predicts likely benign (score 0.0885) — an in-silico prediction, not a clinical call.

GRID2 p.Pro678Ala

c.2032C>G · rs146342092 · VCV2579890

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0885 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.264%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0885	likely benign
REVEL	0.148	moderately benign-leaning
SaProt	LLR -6.22	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 0.047, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 548 kb · p 0.0047 · regional, not allelic
Overall
CADD	23.5	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 0.264% African / African-American · 197/74,492 alleles

Filtering AF 0.234% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.223%

Overall 0.0135% 216/1,604,096 alleles · rare exomes 100/1,451,954 · genomes 116/152,142 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.264%	378
Remaining individualsnot grpmax-eligible	0.0177%	5,636
Admixed American	0.0135%	7,389

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: GRID2
Protein: p.Pro678Ala
Coding: c.2032C>G
MANE Select: NM_001510
dbSNP: rs146342092
Type: single nucleotide variant
Location: chr4:93515250 (GRCh38)
Gene constraint: LOEUF 0.332 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.07 · 6 PDB

Full GRID2 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

GRID2 p.Pro678Leu Uncertain significance ★ ⚠ same residue
GRID2 p.Ala654Thr Pathogenic/Likely pathogenic ★★ same condition
GRID2 p.Ala196Glu Uncertain significance ★★ ⚠ same condition
GRID2 p.Ala21Val Uncertain significance ★★ ⚠ same condition
GRID2 p.Ala574Ser Uncertain significance ★★ ⚠ same condition
GRID2 p.Arg229Gln Uncertain significance ★★ ⚠ same condition
GRID2 p.Arg297Gln Uncertain significance ★★ ⚠ same condition
GRID2 p.Arg439Leu 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/grid2-p-pro678ala (accessed [today's date]).

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