Is TRDN p.Arg93Ser (c.277C>A) pathogenic?

TRDN p.Arg93Ser (c.277C>A) is classified Uncertain significance in TRDN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-02-16). AlphaMissense: likely benign (0.2878); Very rare (popmax 0.00275%, afr); Associated with catecholaminergic polymorphic ventricular tachycardia 1.

What condition is associated with TRDN p.Arg93Ser (c.277C>A)?

TRDN p.Arg93Ser (c.277C>A) is associated with catecholaminergic polymorphic ventricular tachycardia 1 (ClinVar).

How common is TRDN p.Arg93Ser (c.277C>A) in the general population?

TRDN p.Arg93Ser (c.277C>A) is very rare (popmax 0.00275%, afr) (gnomAD).

What do computational predictors say about TRDN p.Arg93Ser (c.277C>A)?

AlphaMissense predicts likely benign (score 0.2878) — an in-silico prediction, not a clinical call.

TRDN p.Arg93Ser

Q: How is Inherited isolated arrhythmogenic cardiomyopathy inherited?

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

c.277C>A · rs370788759 · VCV2168185

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2878 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00275%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

catecholaminergic polymorphic ventricular tachycardia 1

Computational evidence

Protein change
AlphaMissense	0.2878	likely benign
REVEL	0.017	moderately benign-leaning
SaProt	LLR -3.45	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.9	GERP 1.7, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 418 kb · p 0.011 · regional, not allelic
Overall
CADD	23.4	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 0.00275% African / African-American · 2/72,714 alleles

Filtering AF 0.000631% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000486%

Overall 0.00116% 18/1,554,872 alleles · very rare exomes 18/1,404,408 · genomes 0/150,464 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00328%	30,511
African / African-Americangrpmax	0.00275%	36,357
East Asian	0.00235%	42,590
European (non-Finnish)	0.00113%	88,402

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg93Ser
Coding: c.277C>A
MANE Select: NM_006073
dbSNP: rs370788759
Type: single nucleotide variant
Location: chr6:123548568 (GRCh38)
Gene constraint: LOEUF 1.359 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 47.65

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.Arg93Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
TRDN p.Arg93His 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
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-arg93ser (accessed [today's date]).

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