Is RYR1 p.Ala4526Val (c.13577C>T) pathogenic?

RYR1 p.Ala4526Val (c.13577C>T) is classified Uncertain significance in RYR1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-30). AlphaMissense: likely benign (0.068); Very rare (popmax 8.47e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with RYR1 p.Ala4526Val (c.13577C>T)?

RYR1 p.Ala4526Val (c.13577C>T) is associated with Inborn genetic diseases (ClinVar).

How common is RYR1 p.Ala4526Val (c.13577C>T) in the general population?

RYR1 p.Ala4526Val (c.13577C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about RYR1 p.Ala4526Val (c.13577C>T)?

AlphaMissense predicts likely benign (score 0.068) — an in-silico prediction, not a clinical call.

RYR1 p.Ala4526Val

c.13577C>T · VCV3436548

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.068 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.068	likely benign
REVEL	0.384	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP 1.2, phastCons 0.96
Regional constraint	o/e 0.99	unconstrained · MANE · 22 kb · p 0.81 · regional, not allelic
Overall
CADD	14.89	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 8.47e-05% European (non-Finnish) · 1/1,180,038 alleles

Overall 6.2e-05% 1/1,614,028 alleles · very rare exomes 0/1,461,858 · genomes 1/152,170 · 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.Ala4526Val
Coding: c.13577C>T
MANE Select: NM_000540
Type: single nucleotide variant
Location: chr19:38567835 (GRCh38)
Gene constraint: LOEUF 0.644 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 4526: the 'disordered' region

Full RYR1 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

RYR1 p.Ala1318Thr Uncertain significance ★★ same condition
RYR1 p.Ala1587Thr Uncertain significance ★★ same condition
RYR1 p.Ala25Pro Uncertain significance ★★ ⚠ same condition
RYR1 p.Ala365Thr Uncertain significance ★★ ⚠ same condition
RYR1 p.Ala4040Thr Uncertain significance ★★ ⚠ same condition
RYR1 p.Ala4279Val Uncertain significance ★★ ⚠ same condition
RYR1 p.Ala4286Thr Uncertain significance ★★ ⚠ same condition
RYR1 p.Ala4304Thr 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/ryr1-p-ala4526val (accessed [today's date]).

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