Is REST p.Ser1027Ile (c.3080G>T) pathogenic?

REST p.Ser1027Ile (c.3080G>T) is classified Uncertain significance in REST (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-22). AlphaMissense: likely pathogenic (0.5913); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with REST p.Ser1027Ile (c.3080G>T)?

REST p.Ser1027Ile (c.3080G>T) is associated with Inborn genetic diseases (ClinVar).

How common is REST p.Ser1027Ile (c.3080G>T) in the general population?

REST p.Ser1027Ile (c.3080G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about REST p.Ser1027Ile (c.3080G>T)?

AlphaMissense predicts likely pathogenic (score 0.5913) — an in-silico prediction, not a clinical call.

REST p.Ser1027Ile

c.3080G>T · VCV3788282

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5913 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5913	likely pathogenic
REVEL	0.36	indeterminate
SaProt	LLR -9.94	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.3, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 1,930 bp · p 0.0028 · regional, not allelic
Overall
CADD	27.9	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: REST
Protein: p.Ser1027Ile
Coding: c.3080G>T
MANE Select: NM_005612
Type: single nucleotide variant
Location: chr4:56931938 (GRCh38)
Gene constraint: LOEUF 0.16 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 49.53 · 3 PDB
Residue 1027: the 'disordered' region; the 'interaction with rcor1' 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-ser1027ile (accessed [today's date]).

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