Is REST p.Cys415Ser (c.1244G>C) pathogenic?

REST p.Cys415Ser (c.1244G>C) is classified Likely pathogenic in REST (ClinVar, Single submitter, 2 submitters; last evaluated 2024-11-08). AlphaMissense: likely pathogenic (0.9936); Absent from gnomAD v4.1; Associated with autosomal dominant nonsyndromic hearing loss.

What condition is associated with REST p.Cys415Ser (c.1244G>C)?

REST p.Cys415Ser (c.1244G>C) is associated with autosomal dominant nonsyndromic hearing loss, autosomal dominant nonsyndromic hearing loss 27 (ClinVar).

How common is REST p.Cys415Ser (c.1244G>C) in the general population?

REST p.Cys415Ser (c.1244G>C) is absent from gnomAD v4.1 (gnomAD).

How is Rare non-syndromic genetic deafness inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about REST p.Cys415Ser (c.1244G>C)?

AlphaMissense predicts likely pathogenic (score 0.9936) — an in-silico prediction, not a clinical call.

REST p.Cys415Ser

c.1244G>C · rs2109573013 · VCV1686854

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9936 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

autosomal dominant nonsyndromic hearing loss

Computational evidence

Protein change
AlphaMissense	0.9936	likely pathogenic ✓ concordant with ClinVar · top 9% in REST
REVEL	0.354	indeterminate
SaProt	LLR -5.70	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 1.1, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 1,930 bp · p 0.0028 · regional, not allelic
Overall
CADD	24.4	PHRED · no single calibrated threshold — expert panels disagree

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.Cys415Ser
Coding: c.1244G>C
MANE Select: NM_005612
dbSNP: rs2109573013
Type: single nucleotide variant
Location: chr4:56930102 (GRCh38)
Gene constraint: LOEUF 0.16 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 49.53 · 3 PDB
Residue 415: the 'interaction with zfp90' region

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

Disease context

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

Also linked: autosomal dominant nonsyndromic hearing loss 27

For Rare non-syndromic genetic deafness (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Infancy, Neonatal

Similar variants

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
REST p.Asn927Ser Uncertain significance ★★ ⚠ same condition
REST p.Asp139Gly 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-cys415ser (accessed [today's date]).

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