Is TRDN p.Lys412fs (c.1233_1234dup) pathogenic?

TRDN p.Lys412fs (c.12331234dup) is classified Uncertain significance in TRDN (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-05-30). Very rare (popmax 0.00668%, afr); Associated with Cardiovascular phenotype.

How common is TRDN p.Lys412fs (c.1233_1234dup) in the general population?

TRDN p.Lys412fs (c.1233_1234dup) is very rare (popmax 0.00668%, afr) (gnomAD).

TRDN p.Lys412fs

Q: What condition is associated with TRDN p.Lys412fs (c.1233_1234dup)?

TRDN p.Lys412fs (c.1233_1234dup) is associated with Cardiovascular phenotype, catecholaminergic polymorphic ventricular tachycardia 1, catecholaminergic polymorphic ventricular tachycardia 5 (ClinVar).

c.1233_1234dup · rs778198100 · VCV423208

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00668%, afr)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 18 of 41
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.9	GERP 2.3, phastCons 1
Overall
CADD	29.7	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00668% African / African-American · 5/74,884 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00162%

Overall 0.000558% 9/1,613,158 alleles · very rare exomes 7/1,461,004 · genomes 2/152,154 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00668%	14,977
European (non-Finnish)	0.000339%	294,910

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.Lys412fs
Coding: c.1233_1234dup
MANE Select: NM_006073
dbSNP: rs778198100
Type: Duplication
Location: chr6:123377727 (GRCh38)
Gene constraint: LOEUF 1.359 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 47.65
Residue 412: the 'disordered' region

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

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: catecholaminergic polymorphic ventricular tachycardia 1 catecholaminergic polymorphic ventricular tachycardia 5

Similar variants

TRDN p.Ile190fs Pathogenic/Likely pathogenic ★★ same condition
TRDN p.Thr99fs Pathogenic ★★ same condition
TRDN p.Thr573fs Uncertain significance ★★ same condition
TRDN c.1598-6dup Benign/Likely benign ★★ same condition
TRDN c.1805-21_1805-20dup Benign ★★ same condition
TRDN c.1805-21dup Benign/Likely benign ★★ same condition
TRDN c.425-11dup Likely benign ★★ same condition
TRDN p.Asn75fs 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-lys412fs (accessed [today's date]).

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