Is RYR3 p.Asp1069Ala (c.3206A>C) pathogenic?

RYR3 p.Asp1069Ala (c.3206A>C) is classified Uncertain significance in RYR3 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-01-02). AlphaMissense: ambiguous (0.4896); Very rare (popmax 8.48e-05%, nfe); Associated with Epileptic encephalopathy.

What condition is associated with RYR3 p.Asp1069Ala (c.3206A>C)?

RYR3 p.Asp1069Ala (c.3206A>C) is associated with Epileptic encephalopathy (ClinVar).

How common is RYR3 p.Asp1069Ala (c.3206A>C) in the general population?

RYR3 p.Asp1069Ala (c.3206A>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about RYR3 p.Asp1069Ala (c.3206A>C)?

AlphaMissense predicts ambiguous (score 0.4896) — an in-silico prediction, not a clinical call.

RYR3 p.Asp1069Ala

c.3206A>C · rs1272965489 · VCV1026157

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4896 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Conditions

Epileptic encephalopathy

Computational evidence

Protein change
AlphaMissense	0.4896	ambiguous
REVEL	0.793	moderately pathogenic-leaning
SaProt	—	not scored · why
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 2.8, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 325 kb · p 0.099 · regional, not allelic
Overall
CADD	22.8	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 8.48e-05% European (non-Finnish) · 1/1,179,876 alleles

Overall 6.2e-05% 1/1,613,934 alleles · very rare exomes 1/1,461,614 · genomes 0/152,320 · 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: RYR3
Protein: p.Asp1069Ala
Coding: c.3206A>C
MANE Select: NM_001036
dbSNP: rs1272965489
Type: single nucleotide variant
Location: chr15:33635644 (GRCh38)
Gene constraint: LOEUF 0.43 · pLI 1.00 (gnomAD)
Residue 1069: the b30.2/spry 2 domain; the '4 x approximate repeats' region

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

Similar variants

RYR3 c.10758+6C>G Uncertain significance ★★ same condition
RYR3 c.10995+5C>T Uncertain significance ★★ same condition
RYR3 c.12978+3A>G Uncertain significance ★★ same condition
RYR3 p.Ala1179Thr Uncertain significance ★★ ⚠ same condition
RYR3 p.Ala1331Thr Uncertain significance ★★ ⚠ same condition
RYR3 p.Ala1570Thr Uncertain significance ★★ ⚠ same condition
RYR3 p.Ala1579Thr Uncertain significance ★★ ⚠ same condition
RYR3 p.Ala2151Val 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/ryr3-p-asp1069ala (accessed [today's date]).

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