Is TRDN p.Ala366Thr (c.1096G>A) pathogenic?

TRDN p.Ala366Thr (c.1096G>A) is classified Benign/Likely benign in TRDN (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.0632); Low-frequency (popmax 3.94%, afr); Associated with Cardiovascular phenotype.

How common is TRDN p.Ala366Thr (c.1096G>A) in the general population?

TRDN p.Ala366Thr (c.1096G>A) is low-frequency (popmax 3.94%, afr) (gnomAD).

What do computational predictors say about TRDN p.Ala366Thr (c.1096G>A)?

AlphaMissense predicts likely benign (score 0.0632) — an in-silico prediction, not a clinical call.

TRDN p.Ala366Thr

Q: What condition is associated with TRDN p.Ala366Thr (c.1096G>A)?

TRDN p.Ala366Thr (c.1096G>A) is associated with Cardiovascular phenotype, catecholaminergic polymorphic ventricular tachycardia 1, catecholaminergic polymorphic ventricular tachycardia 5 (ClinVar).

c.1096G>A · rs35047281 · VCV227104

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.0632 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 3.94%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.0632	likely benign
REVEL	0.02	moderately benign-leaning
SaProt	LLR -5.94	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.4	GERP -1.2
Regional constraint	o/e 1.09	unconstrained · MANE · 418 kb · p 0.011 · regional, not allelic
Overall
CADD	0.481	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 3.94% African / African-American · 2,942/74,742 alleles

Filtering AF 3.82% ClinGen BA1/BS1 input FAF95, joint · FAF99 3.77%

Overall 0.206% 3,307/1,604,516 alleles · low-frequency exomes 1,553/1,452,506 · genomes 1,754/152,010 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	3.94%	25
Remaining individualsnot grpmax-eligible	0.274%	365
Admixed American	0.247%	404
Middle Eastern	0.0662%	1,510
South Asian	0.00781%	12,806
European (non-Finnish)	0.00323%	30,914

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.Ala366Thr
Coding: c.1096G>A
MANE Select: NM_006073
dbSNP: rs35047281
Type: single nucleotide variant
Location: chr6:123393633 (GRCh38)
Gene constraint: LOEUF 1.359 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 47.65
Residue 366: 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.Ala366= Likely benign ★★ 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-ala366thr (accessed [today's date]).

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