Is RYR2 p.Ala2467Val (c.7400C>T) pathogenic?

RYR2 p.Ala2467Val (c.7400C>T) is classified Likely pathogenic in RYR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-01-12). AlphaMissense: likely pathogenic (0.7895); Absent from gnomAD v4.1; Associated with Cardiovascular phenotype.

What condition is associated with RYR2 p.Ala2467Val (c.7400C>T)?

RYR2 p.Ala2467Val (c.7400C>T) is associated with Cardiovascular phenotype (ClinVar).

How common is RYR2 p.Ala2467Val (c.7400C>T) in the general population?

RYR2 p.Ala2467Val (c.7400C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about RYR2 p.Ala2467Val (c.7400C>T)?

AlphaMissense predicts likely pathogenic (score 0.7895) — an in-silico prediction, not a clinical call.

RYR2 p.Ala2467Val

c.7400C>T · VCV3894655

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7895 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.7895	likely pathogenic ✓ concordant with ClinVar
REVEL	0.704	pathogenic-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this damaging; SaProt makes no call.
Splicing
SpliceAI	Δ0.21	acceptor gain · deltas
Pangolin	Δ0.23	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 132 kb · p 8.2e-16 · regional, not allelic
Overall
CADD	27.3	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

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.Ala2467Val
Coding: c.7400C>T
MANE Select: NM_001035
Type: single nucleotide variant
Location: chr1:237648501 (GRCh38)
Gene constraint: LOEUF 0.424 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Residue 2467: 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

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

Similar variants

RYR2 p.Ala2387Val 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
RYR2 p.Arg2401His Pathogenic/Likely pathogenic ★★ same condition
RYR2 p.Arg4497Cys Pathogenic ★★ same condition
RYR2 p.Glu2636Lys Pathogenic/Likely pathogenic ★★ same condition
RYR2 p.Gly357Ser 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-ala2467val (accessed [today's date]).

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