Is RYR1 p.Arg4306Gln (c.12917G>A) pathogenic?

RYR1 p.Arg4306Gln (c.12917G>A) is classified Uncertain significance in RYR1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-06). AlphaMissense: likely benign (0.1514); Very rare (popmax 0.000958%, nfe); Associated with RYR1-related disorder.

What condition is associated with RYR1 p.Arg4306Gln (c.12917G>A)?

RYR1 p.Arg4306Gln (c.12917G>A) is associated with RYR1-related disorder (ClinVar).

How common is RYR1 p.Arg4306Gln (c.12917G>A) in the general population?

RYR1 p.Arg4306Gln (c.12917G>A) is very rare (popmax 0.000958%, nfe) (gnomAD).

What do computational predictors say about RYR1 p.Arg4306Gln (c.12917G>A)?

AlphaMissense predicts likely benign (score 0.1514) — an in-silico prediction, not a clinical call.

RYR1 p.Arg4306Gln

c.12917G>A · rs2145844700 · VCV1522423

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1514 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000958%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

RYR1-related disorder

Computational evidence

Protein change
AlphaMissense	0.1514	likely benign
REVEL	0.281	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.2	GERP 0.094, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 22 kb · p 0.81 · regional, not allelic
Overall
CADD	21.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.000958% European (non-Finnish) · 8/835,218 alleles

Filtering AF 0.000412% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000298%

Overall 0.000807% 8/991,050 alleles · very rare exomes 8/844,502 · genomes 0/146,548 · joint denominator

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.Arg4306Gln
Coding: c.12917G>A
MANE Select: NM_000540
dbSNP: rs2145844700
Type: single nucleotide variant
Location: chr19:38565251 (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.Arg4306Ter Pathogenic ★ 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-arg4306gln (accessed [today's date]).

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