Is REST p.Pro141Arg (c.422C>G) pathogenic?

REST p.Pro141Arg (c.422C>G) is classified Uncertain significance in REST (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-28). AlphaMissense: likely benign (0.1626); Ultra-rare (popmax 0.0496%, nfe); Associated with REST-related disorder.

What condition is associated with REST p.Pro141Arg (c.422C>G)?

REST p.Pro141Arg (c.422C>G) is associated with REST-related disorder (ClinVar).

How common is REST p.Pro141Arg (c.422C>G) in the general population?

REST p.Pro141Arg (c.422C>G) is ultra-rare (popmax 0.0496%, nfe) (gnomAD).

What do computational predictors say about REST p.Pro141Arg (c.422C>G)?

AlphaMissense predicts likely benign (score 0.1626) — an in-silico prediction, not a clinical call.

REST p.Pro141Arg

c.422C>G · rs138686672 · VCV847313

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1626 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0496%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

REST-related disorder

Computational evidence

Protein change
AlphaMissense	0.1626	likely benign
REVEL	0.212	benign-leaning
SaProt	LLR -6.89	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 6	GERP 2.2, phastCons 0.97
Regional constraint	o/e 0.99	unconstrained · MANE · 624 bp · p 0.87 · regional, not allelic
Overall
CADD	23.5	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 0.0496% European (non-Finnish) · 585/1,179,992 alleles

Filtering AF 0.0462% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0449%

Overall 0.0373% 602/1,614,036 alleles · ultra-rare exomes 576/1,461,790 · genomes 26/152,246 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0496%	2,017
Remaining individualsnot grpmax-eligible	0.0128%	7,812
African / African-American	0.00933%	10,714
Finnishnot grpmax-eligible	0.00312%	32,013

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.Pro141Arg
Coding: c.422C>G
MANE Select: NM_005612
dbSNP: rs138686672
Type: single nucleotide variant
Location: chr4:56911060 (GRCh38)
Gene constraint: LOEUF 0.16 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 49.53 · 3 PDB
Residue 141: the 'disordered' region

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

Disease context

REST-related disorder

Similar variants

REST p.Pro141= Likely benign ★★ same residue
REST p.Asn1080Ser Uncertain significance ★★ ⚠ same condition
REST p.Ile448Thr Uncertain significance ★★ ⚠ same condition
REST p.Met785Thr Uncertain significance ★★ ⚠ same condition
REST p.Thr205Ile Uncertain significance ★★ ⚠ same condition
REST p.Ala127Val Uncertain significance ★ ⚠ same condition
REST p.Cys281Trp Uncertain significance ★ ⚠ same condition
REST p.Ile178Asn 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-pro141arg (accessed [today's date]).

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