Is CTNNA3 p.Pro216Ser (c.646C>T) pathogenic?

CTNNA3 p.Pro216Ser (c.646C>T) is classified Uncertain significance in CTNNA3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-25). AlphaMissense: likely benign (0.0905); Very rare (popmax 0.0022%, sas); Associated with arrhythmogenic right ventricular dysplasia 13.

What condition is associated with CTNNA3 p.Pro216Ser (c.646C>T)?

CTNNA3 p.Pro216Ser (c.646C>T) is associated with arrhythmogenic right ventricular dysplasia 13 (ClinVar).

How common is CTNNA3 p.Pro216Ser (c.646C>T) in the general population?

CTNNA3 p.Pro216Ser (c.646C>T) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about CTNNA3 p.Pro216Ser (c.646C>T)?

AlphaMissense predicts likely benign (score 0.0905) — an in-silico prediction, not a clinical call.

CTNNA3 p.Pro216Ser

Q: How is Inherited isolated arrhythmogenic cardiomyopathy inherited?

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

c.646C>T · rs768170868 · VCV1511743

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0905 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

arrhythmogenic right ventricular dysplasia 13

Computational evidence

Protein change
AlphaMissense	0.0905	likely benign
REVEL	0.172	moderately benign-leaning
SaProt	LLR -8.60	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 5.9	GERP 2.2, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 1,727 kb · p 0.0022 · regional, not allelic
Overall
CADD	18.8	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 0.0022% South Asian · 2/91,036 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000274% 4/1,461,660 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,518
European (non-Finnish)	0.00017%	589,939

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.Pro216Ser
Coding: c.646C>T
MANE Select: NM_013266
dbSNP: rs768170868
Type: single nucleotide variant
Location: chr10:67219804 (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-pro216ser (accessed [today's date]).

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