Is TRDN p.Arg656Lys (c.1967G>A) pathogenic?

TRDN p.Arg656Lys (c.1967G>A) is classified Conflicting classifications of pathogenicity in TRDN (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-09-24). AlphaMissense: likely benign (0.0897); Ultra-rare (popmax 0.0137%, afr); Associated with Cardiovascular phenotype.

What condition is associated with TRDN p.Arg656Lys (c.1967G>A)?

TRDN p.Arg656Lys (c.1967G>A) is associated with Cardiovascular phenotype, catecholaminergic polymorphic ventricular tachycardia 1 (ClinVar).

How common is TRDN p.Arg656Lys (c.1967G>A) in the general population?

TRDN p.Arg656Lys (c.1967G>A) is ultra-rare (popmax 0.0137%, afr) (gnomAD).

What do computational predictors say about TRDN p.Arg656Lys (c.1967G>A)?

AlphaMissense predicts likely benign (score 0.0897) — an in-silico prediction, not a clinical call.

TRDN p.Arg656Lys

c.1967G>A · rs1028703114 · VCV1009723

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0897 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0137%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.0897	likely benign
REVEL	0.023	moderately benign-leaning
SaProt	LLR -3.96	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.8	GERP -1.3, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 418 kb · p 0.011 · regional, not allelic
Overall
CADD	10.97	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 0.0137% African / African-American · 10/72,742 alleles

Filtering AF 0.00743% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00565%

Overall 0.000854% 13/1,521,406 alleles · ultra-rare exomes 8/1,369,430 · genomes 5/151,976 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0137%	7,274
Remaining individualsnot grpmax-eligible	0.00341%	29,364
European (non-Finnish)	8.96e-05%	1,115,958

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.Arg656Lys
Coding: c.1967G>A
MANE Select: NM_006073
dbSNP: rs1028703114
Type: single nucleotide variant
Location: chr6:123252420 (GRCh38)
Gene constraint: LOEUF 1.359 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 47.65
Residue 656: 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

Similar variants

TRDN p.Arg656Gly Conflicting classifications of pathogenicity ★ ⚠ 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-arg656lys (accessed [today's date]).

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