Is RYR1 p.Ala3526Val (c.10577C>T) pathogenic?

RYR1 p.Ala3526Val (c.10577C>T) is classified Uncertain significance in RYR1 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2025-10-29). AlphaMissense: likely benign (0.2209); Very rare (popmax 0.00534%, afr); Associated with King-Denborough syndrome.

What condition is associated with RYR1 p.Ala3526Val (c.10577C>T)?

RYR1 p.Ala3526Val (c.10577C>T) is associated with King-Denborough syndrome, central core myopathy, malignant hyperthermia, susceptibility to, 1 (ClinVar).

How common is RYR1 p.Ala3526Val (c.10577C>T) in the general population?

RYR1 p.Ala3526Val (c.10577C>T) is very rare (popmax 0.00534%, afr) (gnomAD).

What do computational predictors say about RYR1 p.Ala3526Val (c.10577C>T)?

AlphaMissense predicts likely benign (score 0.2209) — an in-silico prediction, not a clinical call.

RYR1 p.Ala3526Val

c.10577C>T · rs374061380 · VCV478154

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.2209 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Conditions

King-Denborough syndrome

Computational evidence

Protein change
AlphaMissense	0.2209	likely benign
REVEL	0.49	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.27 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.7	GERP 2.4, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 39 kb · p 7.8e-08 · regional, not allelic
Overall
CADD	23.6	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 0.00534% African / African-American · 4/74,840 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00149%

Overall 0.00229% 37/1,613,870 alleles · very rare exomes 31/1,461,840 · genomes 6/152,030 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00534%	18,710
European (non-Finnish)	0.00246%	40,689
East Asian	0.00223%	44,884
South Asian	0.0022%	45,539
Finnishnot grpmax-eligible	0.00156%	64,038

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.Ala3526Val
Coding: c.10577C>T
MANE Select: NM_000540
dbSNP: rs374061380
Type: single nucleotide variant
Location: chr19:38525453 (GRCh38)
Gene constraint: LOEUF 0.644 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)

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

Disease context

King-Denborough syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: central core myopathy malignant hyperthermia, susceptibility to, 1 congenital fiber-type disproportion myopathy congenital multicore myopathy with external ophthalmoplegia

Similar variants

RYR1 p.Ala3526= Conflicting classifications of pathogenicity ★ same residue
RYR1 c.10347+1G>A Pathogenic ★★★ same condition
RYR1 c.10348-6C>G Pathogenic ★★★ same condition
RYR1 c.1925+1G>C Likely pathogenic ★★★ same condition
RYR1 c.8310+1G>T Pathogenic ★★★ same condition
RYR1 c.9472+1G>A Pathogenic ★★★ same condition
RYR1 p.Ala152Asp Likely pathogenic ★★★ same condition
RYR1 p.Ala2200Val 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-ala3526val (accessed [today's date]).

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