Is TRDN p.Ala435Val (c.1304C>T) pathogenic?

TRDN p.Ala435Val (c.1304C>T) is classified Conflicting classifications of pathogenicity in TRDN (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-08-04). AlphaMissense: likely benign (0.1173); Ultra-rare (popmax 0.0165%, mid); Associated with catecholaminergic polymorphic ventricular tachycardia 1.

What condition is associated with TRDN p.Ala435Val (c.1304C>T)?

TRDN p.Ala435Val (c.1304C>T) is associated with catecholaminergic polymorphic ventricular tachycardia 1, catecholaminergic polymorphic ventricular tachycardia 5 (ClinVar).

How common is TRDN p.Ala435Val (c.1304C>T) in the general population?

TRDN p.Ala435Val (c.1304C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about TRDN p.Ala435Val (c.1304C>T)?

AlphaMissense predicts likely benign (score 0.1173) — an in-silico prediction, not a clinical call.

TRDN p.Ala435Val

Q: How is Inherited isolated arrhythmogenic cardiomyopathy inherited?

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

c.1304C>T · rs370712881 · VCV532360

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1173 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

catecholaminergic polymorphic ventricular tachycardia 1

Computational evidence

Protein change
AlphaMissense	0.1173	likely benign
REVEL	0.07	moderately benign-leaning
SaProt	LLR -6.98	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 3.7	GERP 2.3, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 418 kb · p 0.011 · regional, not allelic
Overall
CADD	20.9	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

Grpmax group 0.0165% Middle Eastern · 1/6,054 alleles

Filtering AF 0.00624% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00468%

Overall 0.0049% 79/1,612,256 alleles · ultra-rare exomes 66/1,460,144 · genomes 13/152,112 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,054
African / African-American	0.012%	8,324
Remaining individualsnot grpmax-eligible	0.00641%	15,607
South Asian	0.0055%	18,187
European (non-Finnish)	0.00492%	20,327
Admixed American	0.00334%	29,950

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: TRDN
Protein: p.Ala435Val
Coding: c.1304C>T
MANE Select: NM_006073
dbSNP: rs370712881
Type: single nucleotide variant
Location: chr6:123366152 (GRCh38)
Gene constraint: LOEUF 1.359 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 47.65
Residue 435: the 'disordered' region

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

Disease context

catecholaminergic polymorphic ventricular tachycardia 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: catecholaminergic polymorphic ventricular tachycardia 5

For Inherited isolated arrhythmogenic cardiomyopathy (Orphanet):

Inheritance: Autosomal dominant
Onset: No data available

Similar variants

TRDN p.Ala435Glu Uncertain significance ★★ ⚠ same residue
TRDN p.Ala435= Likely benign ★★ same residue
TRDN c.22+1G>T Pathogenic ★★ same condition
TRDN c.22+29A>G Pathogenic ★★ same condition
TRDN c.391+1G>A Likely pathogenic ★★ same condition
TRDN p.Gln205Ter Pathogenic/Likely pathogenic ★★ same condition
TRDN p.Glu168Ter Pathogenic/Likely pathogenic ★★ same condition
TRDN p.Glu181Ter Pathogenic/Likely pathogenic ★★ 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/trdn-p-ala435val (accessed [today's date]).

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