Is RYR3 p.Ala4726Val (c.14177C>T) pathogenic?

RYR3 p.Ala4726Val (c.14177C>T) is classified Uncertain significance in RYR3 (ClinVar, Single submitter, 1 submitter; last evaluated 2017-08-13). AlphaMissense: likely pathogenic (0.9927); Absent from gnomAD v4.1; Associated with Epileptic encephalopathy.

What condition is associated with RYR3 p.Ala4726Val (c.14177C>T)?

RYR3 p.Ala4726Val (c.14177C>T) is associated with Epileptic encephalopathy (ClinVar).

How common is RYR3 p.Ala4726Val (c.14177C>T) in the general population?

RYR3 p.Ala4726Val (c.14177C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about RYR3 p.Ala4726Val (c.14177C>T)?

AlphaMissense predicts likely pathogenic (score 0.9927) — an in-silico prediction, not a clinical call.

RYR3 p.Ala4726Val

c.14177C>T · rs1162778289 · VCV530990

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9927 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Epileptic encephalopathy

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
AlphaMissense	0.9927	likely pathogenic
REVEL	0.862	moderately pathogenic-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this damaging; SaProt makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 7.6	GERP 2.4, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 27 kb · p 0.3 · regional, not allelic
Overall
CADD	26.7	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: RYR3
Protein: p.Ala4726Val
Coding: c.14177C>T
MANE Select: NM_001036
dbSNP: rs1162778289
Type: single nucleotide variant
Location: chr15:33859609 (GRCh38)

Full RYR3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

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/ryr3-p-ala4726val (accessed [today's date]).

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