Is TRDN p.Glu331Lys (c.991G>A) pathogenic?

TRDN p.Glu331Lys (c.991G>A) is classified Uncertain significance in TRDN (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-04-24). AlphaMissense: likely benign (0.1981); Ultra-rare (popmax 0.0122%, afr); Associated with Cardiovascular phenotype.

How common is TRDN p.Glu331Lys (c.991G>A) in the general population?

TRDN p.Glu331Lys (c.991G>A) is ultra-rare (popmax 0.0122%, afr) (gnomAD).

What do computational predictors say about TRDN p.Glu331Lys (c.991G>A)?

AlphaMissense predicts likely benign (score 0.1981) — an in-silico prediction, not a clinical call.

TRDN p.Glu331Lys

Q: What condition is associated with TRDN p.Glu331Lys (c.991G>A)?

TRDN p.Glu331Lys (c.991G>A) is associated with Cardiovascular phenotype, catecholaminergic polymorphic ventricular tachycardia 1, catecholaminergic polymorphic ventricular tachycardia 5 (ClinVar).

c.991G>A · rs763851599 · VCV463682

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1981 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0122%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.1981	likely benign
REVEL	0.07	moderately benign-leaning
SaProt	LLR -7.82	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.87	donor loss at this position · masked 0 · deltas
Pangolin	Δ0.76	loss · gain 0.01 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 5.9	GERP 2.2, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 418 kb · p 0.011 · regional, not allelic
Overall
CADD	25.2	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 0.0122% African / African-American · 9/73,492 alleles

Filtering AF 0.00634% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00475%

Overall 0.000642% 10/1,557,834 alleles · ultra-rare exomes 5/1,405,754 · genomes 5/152,080 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0122%	8,166
Remaining individualsnot grpmax-eligible	0.00166%	60,274

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.Glu331Lys
Coding: c.991G>A
MANE Select: NM_006073
dbSNP: rs763851599
Type: single nucleotide variant
Location: chr6:123438944 (GRCh38)
Gene constraint: LOEUF 1.359 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 47.65
Residue 331: 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.Glu331Asp 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
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-glu331lys (accessed [today's date]).

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