Is CTNNA3 p.Phe154Ser (c.461T>C) pathogenic?

CTNNA3 p.Phe154Ser (c.461T>C) is classified Uncertain significance in CTNNA3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-04-20). AlphaMissense: likely pathogenic (0.5983); Absent from gnomAD v4.1; Associated with arrhythmogenic right ventricular dysplasia 13.

What condition is associated with CTNNA3 p.Phe154Ser (c.461T>C)?

CTNNA3 p.Phe154Ser (c.461T>C) is associated with arrhythmogenic right ventricular dysplasia 13 (ClinVar).

How common is CTNNA3 p.Phe154Ser (c.461T>C) in the general population?

CTNNA3 p.Phe154Ser (c.461T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CTNNA3 p.Phe154Ser (c.461T>C)?

AlphaMissense predicts likely pathogenic (score 0.5983) — an in-silico prediction, not a clinical call.

CTNNA3 p.Phe154Ser

Q: How is Inherited isolated arrhythmogenic cardiomyopathy inherited?

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

c.461T>C · rs1260265238 · VCV2905208

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.5983 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

arrhythmogenic right ventricular dysplasia 13

Computational evidence

Protein change
AlphaMissense	0.5983	likely pathogenic
REVEL	0.255	benign-leaning
SaProt	LLR -9.09	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.3	GERP 1.4, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 1,727 kb · p 0.0022 · regional, not allelic
Overall
CADD	24.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CTNNA3
Protein: p.Phe154Ser
Coding: c.461T>C
MANE Select: NM_013266
dbSNP: rs1260265238
Type: single nucleotide variant
Location: chr10:67521960 (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-phe154ser (accessed [today's date]).

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