Is REST p.Lys452Arg (c.1355A>G) pathogenic?

REST p.Lys452Arg (c.1355A>G) is classified Conflicting classifications of pathogenicity in REST (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-04-22). AlphaMissense: likely benign (0.0939); Ultra-rare (popmax 0.018%, sas); Associated with Inborn genetic diseases.

What condition is associated with REST p.Lys452Arg (c.1355A>G)?

REST p.Lys452Arg (c.1355A>G) is associated with Inborn genetic diseases (ClinVar).

How common is REST p.Lys452Arg (c.1355A>G) in the general population?

REST p.Lys452Arg (c.1355A>G) is ultra-rare (popmax 0.018%, sas) (gnomAD).

What do computational predictors say about REST p.Lys452Arg (c.1355A>G)?

AlphaMissense predicts likely benign (score 0.0939) — an in-silico prediction, not a clinical call.

REST p.Lys452Arg

c.1355A>G · rs555004124 · VCV2654774

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0939 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.018%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0939	likely benign
REVEL	0.082	moderately benign-leaning
SaProt	LLR -8.06	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	GERP 2.2, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 1,930 bp · p 0.0028 · regional, not allelic
Overall
CADD	24.1	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 0.018% South Asian · 16/88,768 alleles

Filtering AF 0.0112% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0092%

Overall 0.000996% 16/1,606,594 alleles · ultra-rare exomes 15/1,454,278 · genomes 1/152,316 · 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.Lys452Arg
Coding: c.1355A>G
MANE Select: NM_005612
dbSNP: rs555004124
Type: single nucleotide variant
Location: chr4:56930213 (GRCh38)
Gene constraint: LOEUF 0.16 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 49.53 · 3 PDB
Residue 452: the 'disordered' region; a UniProt-annotated variant site (in gingf5)

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-lys452arg (accessed [today's date]).

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