Is REST p.Val698Ala (c.2093T>C) pathogenic?

REST p.Val698Ala (c.2093T>C) is classified Uncertain significance in REST (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-13). AlphaMissense: likely benign (0.074); Absent from gnomAD v4.1; Associated with autosomal dominant nonsyndromic hearing loss 27.

How common is REST p.Val698Ala (c.2093T>C) in the general population?

REST p.Val698Ala (c.2093T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about REST p.Val698Ala (c.2093T>C)?

AlphaMissense predicts likely benign (score 0.074) — an in-silico prediction, not a clinical call.

REST p.Val698Ala

Q: What condition is associated with REST p.Val698Ala (c.2093T>C)?

REST p.Val698Ala (c.2093T>C) is associated with autosomal dominant nonsyndromic hearing loss 27, Wilms tumor 6, fibromatosis, gingival, 5 (ClinVar).

c.2093T>C · VCV3590652

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.074 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal dominant nonsyndromic hearing loss 27

Computational evidence

Protein change
AlphaMissense	0.074	likely benign
REVEL	0.013	strongly benign-leaning
SaProt	LLR -6.60	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 -0.3	GERP -2.2
Regional constraint	o/e 1.11	unconstrained · MANE · 1,930 bp · p 0.0028 · regional, not allelic
Overall
CADD	0.019	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: REST
Protein: p.Val698Ala
Coding: c.2093T>C
MANE Select: NM_005612
Type: single nucleotide variant
Location: chr4:56930951 (GRCh38)
Gene constraint: LOEUF 0.16 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 49.53 · 3 PDB
Residue 698: a UniProt-annotated variant site (in gingf5)

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

Disease context

autosomal dominant nonsyndromic hearing loss 27 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Wilms tumor 6 fibromatosis, gingival, 5

Similar variants

REST p.Val698Ile Uncertain significance ★ ⚠ same residue
REST p.Val698Phe Uncertain significance ★ ⚠ 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

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-val698ala (accessed [today's date]).

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