Is REST p.Ala25Ser (c.73G>T) pathogenic?

REST p.Ala25Ser (c.73G>T) is classified Uncertain significance in REST (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-18). AlphaMissense: likely benign (0.1118); Ultra-rare (popmax 0.0117%, amr); Associated with Inborn genetic diseases.

What condition is associated with REST p.Ala25Ser (c.73G>T)?

REST p.Ala25Ser (c.73G>T) is associated with Inborn genetic diseases (ClinVar).

How common is REST p.Ala25Ser (c.73G>T) in the general population?

REST p.Ala25Ser (c.73G>T) is ultra-rare (popmax 0.0117%, amr) (gnomAD).

What do computational predictors say about REST p.Ala25Ser (c.73G>T)?

AlphaMissense predicts likely benign (score 0.1118) — an in-silico prediction, not a clinical call.

REST p.Ala25Ser

c.73G>T · VCV3637064

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1118 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0117%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1118	likely benign
REVEL	0.094	moderately benign-leaning
SaProt	LLR -5.82	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 8.7	GERP 2.2, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 624 bp · p 0.87 · regional, not allelic
Overall
CADD	22.0	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 0.0117% Admixed American · 7/59,986 alleles

Filtering AF 0.00543% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00381%

Overall 0.000496% 8/1,614,034 alleles · ultra-rare exomes 4/1,461,884 · genomes 4/152,150 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0117%	8,569
Remaining individualsnot grpmax-eligible	0.0016%	62,488

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.Ala25Ser
Coding: c.73G>T
MANE Select: NM_005612
Type: single nucleotide variant
Location: chr4:56910711 (GRCh38)
Gene constraint: LOEUF 0.16 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 49.53 · 3 PDB

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.Ala25= Likely benign ★ same residue
REST p.Ala198Val 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
REST p.Asn912Thr 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-ala25ser (accessed [today's date]).

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