Is REST p.Pro413Ala (c.1237C>G) pathogenic?

REST p.Pro413Ala (c.1237C>G) is classified Uncertain significance in REST (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-18). AlphaMissense: likely pathogenic (0.659); Very rare (popmax 0.00267%, afr); Associated with Inborn genetic diseases.

What condition is associated with REST p.Pro413Ala (c.1237C>G)?

REST p.Pro413Ala (c.1237C>G) is associated with Inborn genetic diseases (ClinVar).

How common is REST p.Pro413Ala (c.1237C>G) in the general population?

REST p.Pro413Ala (c.1237C>G) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about REST p.Pro413Ala (c.1237C>G)?

AlphaMissense predicts likely pathogenic (score 0.659) — an in-silico prediction, not a clinical call.

REST p.Pro413Ala

c.1237C>G · VCV4629058

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.659 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.659	likely pathogenic
REVEL	0.042	moderately benign-leaning
SaProt	LLR -9.16	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 4	GERP 1.3, phastCons 1
Regional constraint	o/e 0.49	unconstrained · MANE · 19 kb · p 3.4e-16 · regional, not allelic
Overall
CADD	23.7	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

Grpmax group 0.00267% African / African-American · 2/74,872 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000124% 2/1,613,606 alleles · very rare exomes 0/1,461,440 · genomes 2/152,166 · joint denominator

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.Pro413Ala
Coding: c.1237C>G
MANE Select: NM_005612
Type: single nucleotide variant
Location: chr4:56930095 (GRCh38)
Gene constraint: LOEUF 0.16 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 49.53 · 3 PDB
Residue 413: the 'interaction with zfp90' region

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.Ala198Val Uncertain significance ★★ ⚠ same condition
REST p.Ala25Ser 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-pro413ala (accessed [today's date]).

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