Is REST p.Val466Ile (c.1396G>A) pathogenic?

REST p.Val466Ile (c.1396G>A) is classified Uncertain significance in REST (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-04-15). AlphaMissense: likely benign (0.0758); Ultra-rare (popmax 0.0121%, afr); Associated with Inborn genetic diseases.

What condition is associated with REST p.Val466Ile (c.1396G>A)?

REST p.Val466Ile (c.1396G>A) is associated with Inborn genetic diseases (ClinVar).

How common is REST p.Val466Ile (c.1396G>A) in the general population?

REST p.Val466Ile (c.1396G>A) is ultra-rare (popmax 0.0121%, afr) (gnomAD).

What do computational predictors say about REST p.Val466Ile (c.1396G>A)?

AlphaMissense predicts likely benign (score 0.0758) — an in-silico prediction, not a clinical call.

REST p.Val466Ile

c.1396G>A · rs774421905 · VCV2173590

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0758 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0121%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0758	likely benign
REVEL	0.03	moderately benign-leaning
SaProt	LLR -6.88	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 0.15	GERP -4.4
Regional constraint	o/e 1.11	unconstrained · MANE · 1,930 bp · p 0.0028 · regional, not allelic
Overall
CADD	12.29	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 0.0121% African / African-American · 9/74,606 alleles

Filtering AF 0.00626% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00469%

Overall 0.00124% 20/1,610,550 alleles · ultra-rare exomes 16/1,458,438 · genomes 4/152,112 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0121%	8,290
Ashkenazi Jewishnot grpmax-eligible	0.00339%	29,512
East Asian	0.00223%	44,856
South Asian	0.00222%	44,963
European (non-Finnish)	0.000594%	168,478

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.Val466Ile
Coding: c.1396G>A
MANE Select: NM_005612
dbSNP: rs774421905
Type: single nucleotide variant
Location: chr4:56930254 (GRCh38)
Gene constraint: LOEUF 0.16 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 49.53 · 3 PDB
Residue 466: 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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

REST p.Val466Phe Uncertain significance ★ ⚠ same residue
REST p.Val466= Likely benign ★ same residue
REST p.Ala198Val Uncertain significance ★★ ⚠ same condition
REST p.Ala25Ser Uncertain significance ★★ ⚠ same condition
REST p.Ala642Val Uncertain significance ★★ ⚠ same condition
REST p.Arg199Gly Uncertain significance ★★ ⚠ same condition
REST p.Arg217Cys Uncertain significance ★★ ⚠ same condition
REST p.Asn282Ser 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-val466ile (accessed [today's date]).

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