Is RYR2 p.Pro248Ser (c.742C>T) pathogenic?

RYR2 p.Pro248Ser (c.742C>T) is classified Uncertain significance in RYR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-19). AlphaMissense: likely benign (0.2374); Ultra-rare (popmax 0.0331%, mid); Associated with ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome.

How common is RYR2 p.Pro248Ser (c.742C>T) in the general population?

RYR2 p.Pro248Ser (c.742C>T) is ultra-rare (popmax 0.0331%, mid) (gnomAD).

What do computational predictors say about RYR2 p.Pro248Ser (c.742C>T)?

AlphaMissense predicts likely benign (score 0.2374) — an in-silico prediction, not a clinical call.

RYR2 p.Pro248Ser

Q: What condition is associated with RYR2 p.Pro248Ser (c.742C>T)?

RYR2 p.Pro248Ser (c.742C>T) is associated with ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome (ClinVar).

c.742C>T · VCV3393178

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2374 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0331%, mid)

Conditions

ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome

Computational evidence

Protein change
AlphaMissense	0.2374	likely benign
REVEL	0.519	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.8	GERP 0.79, phastCons 1
Regional constraint	o/e 0.60	unconstrained · MANE · 46 kb · p 1.6e-06 · 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 0.0331% Middle Eastern · 2/6,042 alleles

Filtering AF 0.00584% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00243%

Overall 0.000186% 3/1,613,886 alleles · ultra-rare exomes 3/1,461,566 · genomes 0/152,320 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0331%	3,021
European (non-Finnish)	8.48e-05%	1,179,874

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.Pro248Ser
Coding: c.742C>T
MANE Select: NM_001035
Type: single nucleotide variant
Location: chr1:237388152 (GRCh38)
Gene constraint: LOEUF 0.424 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Residue 248: the mir 3 domain; an α-helix

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

Disease context

ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

RYR2 p.Val3875Leu Likely pathogenic ★★ same condition
RYR2 c.294+3A>G Uncertain significance ★★ same condition
RYR2 c.4161-5T>C Uncertain significance ★★ same condition
RYR2 c.4596+4C>T Uncertain significance ★★ same condition
RYR2 c.4910+3C>G Uncertain significance ★★ same condition
RYR2 c.8590+4A>G Uncertain significance ★★ same condition
RYR2 p.Ala1568Val Uncertain significance ★★ ⚠ same condition
RYR2 p.Ala2632Val 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/ryr2-p-pro248ser (accessed [today's date]).

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