Is RYR2 p.Pro2823Ser (c.8467C>T) pathogenic?

RYR2 p.Pro2823Ser (c.8467C>T) is classified Uncertain significance in RYR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-06). AlphaMissense: likely pathogenic (0.8685); Absent from gnomAD v4.1; Associated with cardiomyopathy.

What condition is associated with RYR2 p.Pro2823Ser (c.8467C>T)?

RYR2 p.Pro2823Ser (c.8467C>T) is associated with cardiomyopathy (ClinVar).

How common is RYR2 p.Pro2823Ser (c.8467C>T) in the general population?

RYR2 p.Pro2823Ser (c.8467C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about RYR2 p.Pro2823Ser (c.8467C>T)?

AlphaMissense predicts likely pathogenic (score 0.8685) — an in-silico prediction, not a clinical call.

RYR2 p.Pro2823Ser

c.8467C>T · rs2148872770 · VCV1172165

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8685 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

cardiomyopathy

Computational evidence

Protein change
AlphaMissense	0.8685	likely pathogenic
REVEL	0.936	strongly 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 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 132 kb · p 8.2e-16 · regional, not allelic
Overall
CADD	24.2	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: RYR2
Protein: p.Pro2823Ser
Coding: c.8467C>T
MANE Select: NM_001035
dbSNP: rs2148872770
Type: single nucleotide variant
Location: chr1:237666542 (GRCh38)
Gene constraint: LOEUF 0.424 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Residue 2823: the '4 x approximate repeats' region; an α-helix

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

Disease context

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

Similar variants

RYR2 p.Arg420Trp Pathogenic ★★ same condition
RYR2 p.Arg4497Cys Pathogenic ★★ same condition
RYR2 p.Asn4763Ser Pathogenic/Likely pathogenic ★★ same condition
RYR2 p.Gly357Ser Pathogenic ★★ same condition
RYR2 p.Met3978Ile Pathogenic/Likely pathogenic ★★ same condition
RYR2 p.Ser2246Leu Pathogenic ★★ same condition
RYR2 c.10554+6C>A Uncertain significance ★★ same condition
RYR2 c.10936-2A>G 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-pro2823ser (accessed [today's date]).

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