Is TRDN p.His541= (c.1623C>T) pathogenic?

TRDN p.His541= (c.1623C>T) is classified Uncertain significance in TRDN (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-12). Very rare (popmax 0.00466%, eas); Associated with catecholaminergic polymorphic ventricular tachycardia 1.

What condition is associated with TRDN p.His541= (c.1623C>T)?

TRDN p.His541= (c.1623C>T) is associated with catecholaminergic polymorphic ventricular tachycardia 1 (ClinVar).

How common is TRDN p.His541= (c.1623C>T) in the general population?

TRDN p.His541= (c.1623C>T) is very rare (popmax 0.00466%, eas) (gnomAD).

TRDN p.His541=

Q: How is Inherited isolated arrhythmogenic cardiomyopathy inherited?

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

c.1623C>T · rs949570014 · VCV2159093

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00466%, eas)

Conditions

catecholaminergic polymorphic ventricular tachycardia 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.23	acceptor loss, 25 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 3.8	GERP -0.85, phastCons 1
Overall
CADD	2.81	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00466% East Asian · 1/21,440 alleles

Overall 0.000283% 3/1,059,432 alleles · very rare exomes 3/907,972 · genomes 0/151,460 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00466%	21,440
Admixed American	0.00382%	26,192
Remaining individualsnot grpmax-eligible	0.0025%	40,012

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.His541=
Coding: c.1623C>T
MANE Select: NM_006073
dbSNP: rs949570014
Type: single nucleotide variant
Location: chr6:123273338 (GRCh38)
Gene constraint: LOEUF 1.359 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 47.65
Residue 541: 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.His541Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
TRDN p.His541Asp Uncertain significance ★ ⚠ same residue
TRDN p.His541Gln Uncertain significance ★ ⚠ same residue
TRDN p.His541Tyr Uncertain significance ★ ⚠ 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

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-his541 (accessed [today's date]).

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