Is REST p.Pro689Ser (c.2065C>T) pathogenic?

REST p.Pro689Ser (c.2065C>T) is classified Uncertain significance in REST (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-03-24). AlphaMissense: likely benign (0.071); Rare (popmax 0.149%, mid); Associated with autosomal dominant nonsyndromic hearing loss 27.

How common is REST p.Pro689Ser (c.2065C>T) in the general population?

REST p.Pro689Ser (c.2065C>T) is rare (popmax 0.149%, mid) (gnomAD).

What do computational predictors say about REST p.Pro689Ser (c.2065C>T)?

AlphaMissense predicts likely benign (score 0.071) — an in-silico prediction, not a clinical call.

REST p.Pro689Ser

Q: What condition is associated with REST p.Pro689Ser (c.2065C>T)?

REST p.Pro689Ser (c.2065C>T) is associated with autosomal dominant nonsyndromic hearing loss 27, Wilms tumor 6, fibromatosis, gingival, 5 (ClinVar).

c.2065C>T · rs149486440 · VCV1021123

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.071 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.149%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal dominant nonsyndromic hearing loss 27

Computational evidence

Protein change
AlphaMissense	0.071	likely benign
REVEL	0.015	strongly benign-leaning
SaProt	LLR -9.00	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 -9.6	GERP -2.5
Regional constraint	o/e 1.11	unconstrained · MANE · 1,930 bp · p 0.0028 · regional, not allelic
Overall
CADD	4.769	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 0.149% Middle Eastern · 9/6,058 alleles

Filtering AF 0.0774% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0579%

Overall 0.0156% 252/1,613,562 alleles · rare exomes 225/1,461,542 · genomes 27/152,020 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.149%	673
European (non-Finnish)	0.0188%	5,314
Admixed American	0.015%	6,666
Remaining individualsnot grpmax-eligible	0.0096%	10,416
African / African-American	0.00534%	18,737
Finnishnot grpmax-eligible	0.00312%	32,007

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.Pro689Ser
Coding: c.2065C>T
MANE Select: NM_005612
dbSNP: rs149486440
Type: single nucleotide variant
Location: chr4:56930923 (GRCh38)
Gene constraint: LOEUF 0.16 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 49.53 · 3 PDB
Residue 689: 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.Pro689Leu 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-pro689ser (accessed [today's date]).

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