Is RYR3 p.Ala4626Val (c.13877C>T) pathogenic?

RYR3 p.Ala4626Val (c.13877C>T) is classified Conflicting classifications of pathogenicity in RYR3 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-08-28). AlphaMissense: likely benign (0.1016); Ultra-rare (popmax 0.0663%, mid); Associated with Epileptic encephalopathy.

What condition is associated with RYR3 p.Ala4626Val (c.13877C>T)?

RYR3 p.Ala4626Val (c.13877C>T) is associated with Epileptic encephalopathy (ClinVar).

How common is RYR3 p.Ala4626Val (c.13877C>T) in the general population?

RYR3 p.Ala4626Val (c.13877C>T) is ultra-rare (popmax 0.0663%, mid) (gnomAD).

What do computational predictors say about RYR3 p.Ala4626Val (c.13877C>T)?

AlphaMissense predicts likely benign (score 0.1016) — an in-silico prediction, not a clinical call.

RYR3 p.Ala4626Val

c.13877C>T · rs202096363 · VCV854755

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1016 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0663%, mid)

Missense predictors

0/2 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	0.1016	likely benign
REVEL	0.283	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 3.3	GERP 1.5, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 27 kb · p 0.3 · regional, not allelic
Overall
CADD	22.6	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 0.0663% Middle Eastern · 4/6,036 alleles

Filtering AF 0.0226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0136%

Overall 0.0101% 162/1,609,482 alleles · ultra-rare exomes 143/1,457,194 · genomes 19/152,288 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0663%	1,509
Admixed American	0.0238%	4,206
Remaining individualsnot grpmax-eligible	0.0128%	7,795
European (non-Finnish)	0.0108%	9,280
South Asian	0.00557%	17,959
East Asian	0.00446%	22,399
African / African-American	0.00267%	37,401

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: RYR3
Protein: p.Ala4626Val
Coding: c.13877C>T
MANE Select: NM_001036
dbSNP: rs202096363
Type: single nucleotide variant
Location: chr15:33854782 (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-ala4626val (accessed [today's date]).

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