Is TRDN p.Val565Ile (c.1693G>A) pathogenic?

TRDN p.Val565Ile (c.1693G>A) is classified Uncertain significance in TRDN (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-24). AlphaMissense: likely benign (0.0932); Very rare (popmax 0.00719%, eas); Associated with catecholaminergic polymorphic ventricular tachycardia 1.

What condition is associated with TRDN p.Val565Ile (c.1693G>A)?

TRDN p.Val565Ile (c.1693G>A) is associated with catecholaminergic polymorphic ventricular tachycardia 1 (ClinVar).

How common is TRDN p.Val565Ile (c.1693G>A) in the general population?

TRDN p.Val565Ile (c.1693G>A) is very rare (popmax 0.00719%, eas) (gnomAD).

What do computational predictors say about TRDN p.Val565Ile (c.1693G>A)?

AlphaMissense predicts likely benign (score 0.0932) — an in-silico prediction, not a clinical call.

TRDN p.Val565Ile

Q: How is Inherited isolated arrhythmogenic cardiomyopathy inherited?

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

c.1693G>A · rs565178454 · VCV1001452

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0932 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00719%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

catecholaminergic polymorphic ventricular tachycardia 1

Computational evidence

Protein change
AlphaMissense	0.0932	likely benign
REVEL	0.011	strongly benign-leaning
SaProt	LLR -7.72	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.25	donor gain · deltas
Constraint at this position
Conservation	phyloP -1.3	GERP -0.27
Regional constraint	o/e 1.09	unconstrained · MANE · 418 kb · p 0.011 · regional, not allelic
Overall
CADD	16.24	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 0.00719% East Asian · 3/41,712 alleles

Filtering AF 0.00191% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00103%

Overall 0.000325% 5/1,539,962 alleles · very rare exomes 2/1,388,110 · genomes 3/151,852 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00719%	13,904
African / African-American	0.00138%	72,568
European (non-Finnish)	8.75e-05%	1,143,448

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.Val565Ile
Coding: c.1693G>A
MANE Select: NM_006073
dbSNP: rs565178454
Type: single nucleotide variant
Location: chr6:123271166 (GRCh38)
Gene constraint: LOEUF 1.359 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 47.65
Residue 565: 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

For Inherited isolated arrhythmogenic cardiomyopathy (Orphanet):

Inheritance: Autosomal dominant
Onset: No data available

Similar variants

TRDN p.Val565= 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
TRDN p.Lys177Ter 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-val565ile (accessed [today's date]).

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