Is RYR2 p.Ile4635Val (c.13903A>G) pathogenic?

RYR2 p.Ile4635Val (c.13903A>G) is classified Uncertain significance in RYR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-06). AlphaMissense: likely benign (0.2542); Absent from gnomAD v4.1; Associated with cardiomyopathy.

What condition is associated with RYR2 p.Ile4635Val (c.13903A>G)?

RYR2 p.Ile4635Val (c.13903A>G) is associated with cardiomyopathy (ClinVar).

How common is RYR2 p.Ile4635Val (c.13903A>G) in the general population?

RYR2 p.Ile4635Val (c.13903A>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about RYR2 p.Ile4635Val (c.13903A>G)?

AlphaMissense predicts likely benign (score 0.2542) — an in-silico prediction, not a clinical call.

RYR2 p.Ile4635Val

c.13903A>G · rs1558429505 · VCV629096

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2542 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

cardiomyopathy

Computational evidence

Protein change
AlphaMissense	0.2542	likely benign
REVEL	0.496	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 8	GERP 2.1, phastCons 1
Regional constraint	o/e 0.36	constrained · MANE · 5,796 bp · p 8.5e-11 · regional, not allelic
Overall
CADD	20.8	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

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: RYR2
Protein: p.Ile4635Val
Coding: c.13903A>G
MANE Select: NM_001035
dbSNP: rs1558429505
Type: single nucleotide variant
Location: chr1:237793987 (GRCh38)
Gene constraint: LOEUF 0.424 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Residue 4635: an α-helix

Full RYR2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

cardiomyopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

RYR2 p.Ile4635Asn Conflicting classifications of pathogenicity ★ ⚠ same residue
RYR2 p.Arg420Trp Pathogenic ★★ same condition
RYR2 p.Arg4497Cys Pathogenic ★★ same condition
RYR2 p.Asn4763Ser Pathogenic/Likely pathogenic ★★ same condition
RYR2 p.Gly357Ser Pathogenic ★★ same condition
RYR2 p.Met3978Ile Pathogenic/Likely pathogenic ★★ same condition
RYR2 p.Ser2246Leu Pathogenic ★★ same condition
RYR2 c.10554+6C>A 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/ryr2-p-ile4635val (accessed [today's date]).

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