Is REST p.Val485Ala (c.1454T>C) pathogenic?

REST p.Val485Ala (c.1454T>C) is classified Uncertain significance in REST (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-28). AlphaMissense: likely benign (0.1023); Ultra-rare (popmax 0.0242%, sas).

How common is REST p.Val485Ala (c.1454T>C) in the general population?

REST p.Val485Ala (c.1454T>C) is ultra-rare (popmax 0.0242%, sas) (gnomAD).

What do computational predictors say about REST p.Val485Ala (c.1454T>C)?

AlphaMissense predicts likely benign (score 0.1023) — an in-silico prediction, not a clinical call.

REST p.Val485Ala

c.1454T>C · rs757792826 · VCV2894171

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1023 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0242%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1023	likely benign
REVEL	0.042	moderately benign-leaning
SaProt	LLR -6.79	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 -1	GERP -2.9
Regional constraint	o/e 1.11	unconstrained · MANE · 1,930 bp · p 0.0028 · regional, not allelic
Overall
CADD	2.076	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 0.0242% South Asian · 22/91,080 alleles

Filtering AF 0.0163% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0137%

Overall 0.00142% 23/1,614,054 alleles · ultra-rare exomes 21/1,461,756 · genomes 2/152,298 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0242%	4,140
European (non-Finnish)	8.47e-05%	1,180,006

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.Val485Ala
Coding: c.1454T>C
MANE Select: NM_005612
dbSNP: rs757792826
Type: single nucleotide variant
Location: chr4:56930312 (GRCh38)
Gene constraint: LOEUF 0.16 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 49.53 · 3 PDB
Residue 485: the 'disordered' region; a UniProt-annotated variant site (in gingf5)

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

Similar variants

REST p.Val485Met Likely benign ★★ same residue
REST p.Ala198Val Uncertain significance ★★ ⚠ same type
REST p.Ala25Ser Uncertain significance ★★ ⚠ same type
REST p.Ala637Ser Uncertain significance ★★ ⚠ same type
REST p.Ala642Val Uncertain significance ★★ ⚠ same type
REST p.Ala678Ser Uncertain significance ★★ ⚠ same type
REST p.Ala998Thr Uncertain significance ★★ ⚠ same type
REST p.Arg199Gly 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/rest-p-val485ala (accessed [today's date]).

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