Is CTNNA3 p.Lys681Glu (c.2041A>G) pathogenic?

CTNNA3 p.Lys681Glu (c.2041A>G) is classified Uncertain significance in CTNNA3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-23). AlphaMissense: likely benign (0.3046); Very rare (popmax 0.00373%, nfe); Associated with arrhythmogenic right ventricular dysplasia 13.

What condition is associated with CTNNA3 p.Lys681Glu (c.2041A>G)?

CTNNA3 p.Lys681Glu (c.2041A>G) is associated with arrhythmogenic right ventricular dysplasia 13 (ClinVar).

How common is CTNNA3 p.Lys681Glu (c.2041A>G) in the general population?

CTNNA3 p.Lys681Glu (c.2041A>G) is very rare (popmax 0.00373%, nfe) (gnomAD).

What do computational predictors say about CTNNA3 p.Lys681Glu (c.2041A>G)?

AlphaMissense predicts likely benign (score 0.3046) — an in-silico prediction, not a clinical call.

CTNNA3 p.Lys681Glu

Q: How is Inherited isolated arrhythmogenic cardiomyopathy inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.2041A>G · rs142116698 · VCV1038290

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3046 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00373%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

arrhythmogenic right ventricular dysplasia 13

Computational evidence

Protein change
AlphaMissense	0.3046	likely benign
REVEL	0.12	moderately benign-leaning
SaProt	LLR -6.26	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.2, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 1,727 kb · p 0.0022 · regional, not allelic
Overall
CADD	25.6	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 and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00373% European (non-Finnish) · 44/1,179,768 alleles

Filtering AF 0.00283% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00252%

Overall 0.00308% 45/1,461,362 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00373%	26,813
Remaining individualsnot grpmax-eligible	0.0016%	62,478

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: CTNNA3
Protein: p.Lys681Glu
Coding: c.2041A>G
MANE Select: NM_013266
dbSNP: rs142116698
Type: single nucleotide variant
Location: chr10:66069426 (GRCh38)
Gene constraint: LOEUF 0.875 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 81.65

Full CTNNA3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

arrhythmogenic right ventricular dysplasia 13 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Inherited isolated arrhythmogenic cardiomyopathy (Orphanet):

Inheritance: Autosomal dominant
Onset: No data available

Similar variants

CTNNA3 c.100-7A>G Uncertain significance ★★ same condition
CTNNA3 c.843+1G>T Uncertain significance ★★ same condition
CTNNA3 p.Ala124Thr Uncertain significance ★★ ⚠ same condition
CTNNA3 p.Ala130Pro Uncertain significance ★★ ⚠ same condition
CTNNA3 p.Ala131Val Uncertain significance ★★ same condition
CTNNA3 p.Ala165Thr Uncertain significance ★★ ⚠ same condition
CTNNA3 p.Ala188Val Uncertain significance ★★ ⚠ same condition
CTNNA3 p.Ala224Pro 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/ctnna3-p-lys681glu (accessed [today's date]).

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