Is RYR1 p.Ile1426Val (c.4276A>G) pathogenic?

RYR1 p.Ile1426Val (c.4276A>G) is classified Uncertain significance in RYR1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-04-03). AlphaMissense: ambiguous (0.4811); Very rare (popmax 0.000254%, nfe); Associated with RYR1-related disorder.

What condition is associated with RYR1 p.Ile1426Val (c.4276A>G)?

RYR1 p.Ile1426Val (c.4276A>G) is associated with RYR1-related disorder (ClinVar).

How common is RYR1 p.Ile1426Val (c.4276A>G) in the general population?

RYR1 p.Ile1426Val (c.4276A>G) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about RYR1 p.Ile1426Val (c.4276A>G)?

AlphaMissense predicts ambiguous (score 0.4811) — an in-silico prediction, not a clinical call.

RYR1 p.Ile1426Val

c.4276A>G · rs1968671799 · VCV2435598

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4811 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Conditions

RYR1-related disorder

Computational evidence

Protein change
AlphaMissense	0.4811	ambiguous
REVEL	0.515	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.2	GERP 2.1, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 49 kb · p 8.1e-10 · regional, not allelic
Overall
CADD	19.12	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

Grpmax group 0.000254% European (non-Finnish) · 3/1,180,048 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,613,756 alleles · very rare exomes 2/1,461,548 · genomes 1/152,208 · 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: RYR1
Protein: p.Ile1426Val
Coding: c.4276A>G
MANE Select: NM_000540
dbSNP: rs1968671799
Type: single nucleotide variant
Location: chr19:38475433 (GRCh38)
Gene constraint: LOEUF 0.644 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 1426: the b30.2/spry 3 domain; the '6 x approximate repeats' region

Full RYR1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

RYR1-related disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

RYR1 c.10627-1G>C Pathogenic/Likely pathogenic ★★ same condition
RYR1 c.14647-1G>C Likely pathogenic ★★ same condition
RYR1 c.14869-1G>T Pathogenic/Likely pathogenic ★★ same condition
RYR1 c.2683-1G>A Pathogenic/Likely pathogenic ★★ same condition
RYR1 c.2870+1G>A Pathogenic/Likely pathogenic ★★ same condition
RYR1 c.3381+1G>A Pathogenic ★★ same condition
RYR1 c.4935-2A>T Likely pathogenic ★★ same condition
RYR1 c.6127+1G>A Pathogenic/Likely pathogenic ★★ 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/ryr1-p-ile1426val (accessed [today's date]).

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