Is RYR2 p.Ser381= (c.1143C>T) pathogenic?

RYR2 p.Ser381= (c.1143C>T) is classified Benign/Likely benign in RYR2 (ClinVar, Multiple submitters, 13 submitters; last evaluated 2026-01-19). Rare (popmax 0.345%, afr); Associated with Cardiovascular phenotype.

What condition is associated with RYR2 p.Ser381= (c.1143C>T)?

RYR2 p.Ser381= (c.1143C>T) is associated with Cardiovascular phenotype, cardiomyopathy, catecholaminergic polymorphic ventricular tachycardia 1 (ClinVar).

How common is RYR2 p.Ser381= (c.1143C>T) in the general population?

RYR2 p.Ser381= (c.1143C>T) is rare (popmax 0.345%, afr) (gnomAD).

RYR2 p.Ser381=

c.1143C>T · rs368844286 · VCV43710

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 13 submitters

gnomAD v4.1

Rare

rare (popmax 0.345%, afr)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -12	GERP -3.6
Overall
CADD	0.081	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.345% African / African-American · 257/74,466 alleles

Filtering AF 0.31% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.297%

Overall 0.02% 319/1,594,350 alleles · rare exomes 165/1,442,274 · genomes 154/152,076 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.345%	290
Middle Eastern	0.0502%	1,993
Remaining individualsnot grpmax-eligible	0.034%	2,938
Admixed American	0.0339%	2,950
South Asian	0.0023%	43,449
European (non-Finnish)	0.00137%	73,045

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: RYR2
Protein: p.Ser381=
Coding: c.1143C>T
MANE Select: NM_001035
dbSNP: rs368844286
Type: single nucleotide variant
Location: chr1:237441456 (GRCh38)
Gene constraint: LOEUF 0.424 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Residue 381: the mir 5 domain

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

Disease context

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

Also linked: cardiomyopathy catecholaminergic polymorphic ventricular tachycardia 1 catecholaminergic polymorphic ventricular tachycardia

Similar variants

RYR2 p.Ala2387Thr Pathogenic/Likely pathogenic ★★ same condition
RYR2 p.Ala2387Val Pathogenic/Likely pathogenic ★★ same condition
RYR2 p.Ala391Asp Likely pathogenic ★★ same condition
RYR2 p.Ala4091Val Pathogenic/Likely pathogenic ★★ same condition
RYR2 p.Ala4510Pro Pathogenic/Likely pathogenic ★★ same condition
RYR2 p.Ala77Val Pathogenic/Likely pathogenic ★★ same condition
RYR2 p.Arg169Gln Pathogenic/Likely pathogenic ★★ same condition
RYR2 p.Arg169Leu 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/ryr2-p-ser381 (accessed [today's date]).

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