Is CTNNA3 p.Arg628Pro (c.1883G>C) pathogenic?

CTNNA3 p.Arg628Pro (c.1883G>C) is classified Uncertain significance in CTNNA3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-06). AlphaMissense: likely pathogenic (0.9636); Very rare (popmax 8.51e-05%, nfe); Associated with arrhythmogenic right ventricular dysplasia 13.

What condition is associated with CTNNA3 p.Arg628Pro (c.1883G>C)?

CTNNA3 p.Arg628Pro (c.1883G>C) is associated with arrhythmogenic right ventricular dysplasia 13 (ClinVar).

How common is CTNNA3 p.Arg628Pro (c.1883G>C) in the general population?

CTNNA3 p.Arg628Pro (c.1883G>C) is very rare (popmax 8.51e-05%, nfe) (gnomAD).

What do computational predictors say about CTNNA3 p.Arg628Pro (c.1883G>C)?

AlphaMissense predicts likely pathogenic (score 0.9636) — an in-silico prediction, not a clinical call.

CTNNA3 p.Arg628Pro

Q: How is Inherited isolated arrhythmogenic cardiomyopathy inherited?

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

c.1883G>C · VCV3652244

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9636 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.51e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

arrhythmogenic right ventricular dysplasia 13

Computational evidence

Protein change
AlphaMissense	0.9636	likely pathogenic · top 6% in CTNNA3
REVEL	0.416	indeterminate
SaProt	LLR -11.35	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.3, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 1,727 kb · p 0.0022 · regional, not allelic
Overall
CADD	33.0	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 and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.51e-05% European (non-Finnish) · 1/1,175,112 alleles

Overall 6.9e-05% 1/1,449,158 alleles · very rare

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.Arg628Pro
Coding: c.1883G>C
MANE Select: NM_013266
Type: single nucleotide variant
Location: chr10:66280471 (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 p.Arg628Gln Uncertain significance ★★ ⚠ same residue
CTNNA3 p.Arg628Leu Uncertain significance ★ ⚠ same residue
CTNNA3 p.Arg628Trp Uncertain significance ★ ⚠ same residue
CTNNA3 p.Arg628= Likely benign ★ same residue
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

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-arg628pro (accessed [today's date]).

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