Is RYR1 p.Gly3826Val (c.11477G>T) pathogenic?

RYR1 p.Gly3826Val (c.11477G>T) is classified Uncertain significance in RYR1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-22). AlphaMissense: likely pathogenic (0.7823); Ultra-rare (popmax 0.0217%, amr); Associated with RYR1-related disorder.

What condition is associated with RYR1 p.Gly3826Val (c.11477G>T)?

RYR1 p.Gly3826Val (c.11477G>T) is associated with RYR1-related disorder (ClinVar).

How common is RYR1 p.Gly3826Val (c.11477G>T) in the general population?

RYR1 p.Gly3826Val (c.11477G>T) is ultra-rare (popmax 0.0217%, amr) (gnomAD).

What do computational predictors say about RYR1 p.Gly3826Val (c.11477G>T)?

AlphaMissense predicts likely pathogenic (score 0.7823) — an in-silico prediction, not a clinical call.

RYR1 p.Gly3826Val

c.11477G>T · rs1393018982 · VCV1434213

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7823 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0217%, amr)

Missense predictors

2/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

RYR1-related disorder

Computational evidence

Protein change
AlphaMissense	0.7823	likely pathogenic
REVEL	0.812	moderately pathogenic-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this damaging; SaProt makes no call.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 39 kb · p 7.8e-08 · regional, not allelic
Overall
CADD	23.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0217% Admixed American · 13/59,992 alleles

Filtering AF 0.0127% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0101%

Overall 0.000867% 14/1,613,996 alleles · ultra-rare exomes 4/1,461,842 · genomes 10/152,154 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0217%	4,615
Remaining individualsnot grpmax-eligible	0.0016%	62,482

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.Gly3826Val
Coding: c.11477G>T
MANE Select: NM_000540
dbSNP: rs1393018982
Type: single nucleotide variant
Location: chr19:38535353 (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

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

Similar variants

RYR1 p.Gly3826= Likely benign ★ same residue
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

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-gly3826val (accessed [today's date]).

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