Is REST p.Ala620Val (c.1859C>T) pathogenic?

REST p.Ala620Val (c.1859C>T) is classified Uncertain significance in REST (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-21). AlphaMissense: likely benign (0.0773); Very rare (popmax 0.0027%, afr); Associated with Inborn genetic diseases.

What condition is associated with REST p.Ala620Val (c.1859C>T)?

REST p.Ala620Val (c.1859C>T) is associated with Inborn genetic diseases (ClinVar).

How common is REST p.Ala620Val (c.1859C>T) in the general population?

REST p.Ala620Val (c.1859C>T) is very rare (popmax 0.0027%, afr) (gnomAD).

What do computational predictors say about REST p.Ala620Val (c.1859C>T)?

AlphaMissense predicts likely benign (score 0.0773) — an in-silico prediction, not a clinical call.

REST p.Ala620Val

c.1859C>T · VCV3944654

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0773 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0027%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0773	likely benign
REVEL	0.039	moderately benign-leaning
SaProt	LLR -4.71	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 -1.2	GERP -3.7
Regional constraint	o/e 1.11	unconstrained · MANE · 1,930 bp · p 0.0028 · regional, not allelic
Overall
CADD	0.644	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 0.0027% African / African-American · 2/74,168 alleles

Filtering AF 0.000448% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000168%

Overall 0.000623% 10/1,605,132 alleles · very rare exomes 9/1,452,998 · genomes 1/152,134 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0027%	37,084
East Asian	0.00223%	44,840
Admixed American	0.00175%	57,304
South Asian	0.00112%	89,324
European (non-Finnish)	0.000425%	235,563

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.Ala620Val
Coding: c.1859C>T
MANE Select: NM_005612
Type: single nucleotide variant
Location: chr4:56930717 (GRCh38)
Gene constraint: LOEUF 0.16 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 49.53 · 3 PDB
Residue 620: 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.Ala620= 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
REST p.Asn390Ser 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-ala620val (accessed [today's date]).

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