Is REST p.Val628Met (c.1882G>A) pathogenic?

REST p.Val628Met (c.1882G>A) is classified Uncertain significance in REST (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-03). AlphaMissense: likely benign (0.0763); Very rare (popmax 0.00223%, eas); Associated with Wilms tumor 6.

What condition is associated with REST p.Val628Met (c.1882G>A)?

REST p.Val628Met (c.1882G>A) is associated with Wilms tumor 6 (ClinVar).

How common is REST p.Val628Met (c.1882G>A) in the general population?

REST p.Val628Met (c.1882G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about REST p.Val628Met (c.1882G>A)?

AlphaMissense predicts likely benign (score 0.0763) — an in-silico prediction, not a clinical call.

REST p.Val628Met

c.1882G>A · rs538702285 · VCV2444866

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0763 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Wilms tumor 6

Computational evidence

Protein change
AlphaMissense	0.0763	likely benign
REVEL	0.011	strongly benign-leaning
SaProt	LLR -3.46	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 -6.6	GERP -3.2
Regional constraint	o/e 1.11	unconstrained · MANE · 1,930 bp · p 0.0028 · regional, not allelic
Overall
CADD	0.016	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 0.00223% East Asian · 1/44,790 alleles

Overall 0.000125% 2/1,601,492 alleles · very rare exomes 1/1,449,230 · genomes 1/152,262 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,790
Remaining individualsnot grpmax-eligible	0.00162%	61,816

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: REST
Protein: p.Val628Met
Coding: c.1882G>A
MANE Select: NM_005612
dbSNP: rs538702285
Type: single nucleotide variant
Location: chr4:56930740 (GRCh38)
Gene constraint: LOEUF 0.16 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 49.53 · 3 PDB
Residue 628: the 'disordered' region; a UniProt-annotated variant site (in gingf5)

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

Disease context

Wilms tumor 6 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

REST p.Val628= Likely benign ★ same residue
REST p.Ala678Ser Uncertain significance ★★ ⚠ same condition
REST p.Ala998Thr Uncertain significance ★★ ⚠ same condition
REST p.Arg246Gln Uncertain significance ★★ ⚠ same condition
REST p.Arg433Gln Uncertain significance ★★ ⚠ same condition
REST p.Asn1080Ser Uncertain significance ★★ ⚠ same condition
REST p.Asn914Ser Uncertain significance ★★ ⚠ same condition
REST p.Asn927Ser 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/rest-p-val628met (accessed [today's date]).

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