Is REST p.Pro103Arg (c.308C>G) pathogenic?

REST p.Pro103Arg (c.308C>G) is classified Uncertain significance in REST (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-05). AlphaMissense: likely benign (0.1525); Ultra-rare (popmax 0.0245%, eas); Associated with Inborn genetic diseases.

What condition is associated with REST p.Pro103Arg (c.308C>G)?

REST p.Pro103Arg (c.308C>G) is associated with Inborn genetic diseases (ClinVar).

How common is REST p.Pro103Arg (c.308C>G) in the general population?

REST p.Pro103Arg (c.308C>G) is ultra-rare (popmax 0.0245%, eas) (gnomAD).

What do computational predictors say about REST p.Pro103Arg (c.308C>G)?

AlphaMissense predicts likely benign (score 0.1525) — an in-silico prediction, not a clinical call.

REST p.Pro103Arg

c.308C>G · rs751894476 · VCV1407768

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1525 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0245%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1525	likely benign
REVEL	0.058	moderately benign-leaning
SaProt	LLR -6.55	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 3.3	GERP 2.1, phastCons 0.14
Regional constraint	o/e 0.99	unconstrained · MANE · 624 bp · p 0.87 · regional, not allelic
Overall
CADD	18.0	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 0.0245% East Asian · 11/44,894 alleles

Filtering AF 0.0137% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0106%

Overall 0.000743% 12/1,613,994 alleles · ultra-rare exomes 10/1,461,890 · genomes 2/152,104 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0245%	4,081
Remaining individualsnot grpmax-eligible	0.0016%	62,486

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.Pro103Arg
Coding: c.308C>G
MANE Select: NM_005612
dbSNP: rs751894476
Type: single nucleotide variant
Location: chr4:56910946 (GRCh38)
Gene constraint: LOEUF 0.16 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 49.53 · 3 PDB
Residue 103: the 'interaction with sin3a' region; the 'disordered' 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.Pro103Thr Uncertain significance ★★ ⚠ same residue
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

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-pro103arg (accessed [today's date]).

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