Is REST p.Asp219Glu (c.657C>G) pathogenic?

REST p.Asp219Glu (c.657C>G) is classified Uncertain significance in REST (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-17). AlphaMissense: likely pathogenic (0.6245); Absent from gnomAD v4.1; Associated with autosomal dominant nonsyndromic hearing loss 27.

How common is REST p.Asp219Glu (c.657C>G) in the general population?

REST p.Asp219Glu (c.657C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about REST p.Asp219Glu (c.657C>G)?

AlphaMissense predicts likely pathogenic (score 0.6245) — an in-silico prediction, not a clinical call.

REST p.Asp219Glu

Q: What condition is associated with REST p.Asp219Glu (c.657C>G)?

REST p.Asp219Glu (c.657C>G) is associated with autosomal dominant nonsyndromic hearing loss 27, Wilms tumor 6, fibromatosis, gingival, 5 (ClinVar).

c.657C>G · VCV3590639

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6245 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal dominant nonsyndromic hearing loss 27

Computational evidence

Protein change
AlphaMissense	0.6245	likely pathogenic
REVEL	0.164	moderately benign-leaning
SaProt	LLR -4.62	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.1	GERP -3.4, phastCons 0.001
Regional constraint	o/e 0.49	unconstrained · MANE · 19 kb · p 3.4e-16 · regional, not allelic
Overall
CADD	19.28	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.Asp219Glu
Coding: c.657C>G
MANE Select: NM_005612
Type: single nucleotide variant
Location: chr4:56911295 (GRCh38)
Gene constraint: LOEUF 0.16 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 49.53 · 3 PDB
Residue 219: 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 27 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Wilms tumor 6 fibromatosis, gingival, 5

Similar variants

REST p.Asp219Gly 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
REST p.Asn927Ser 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-asp219glu (accessed [today's date]).

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