Is TRDN p.Val66Ile (c.196G>A) pathogenic?

TRDN p.Val66Ile (c.196G>A) is classified Uncertain significance in TRDN (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-10-10). AlphaMissense: likely benign (0.1732); Ultra-rare (popmax 0.0571%, sas); Associated with Cardiovascular phenotype.

What condition is associated with TRDN p.Val66Ile (c.196G>A)?

TRDN p.Val66Ile (c.196G>A) is associated with Cardiovascular phenotype, catecholaminergic polymorphic ventricular tachycardia 1 (ClinVar).

How common is TRDN p.Val66Ile (c.196G>A) in the general population?

TRDN p.Val66Ile (c.196G>A) is ultra-rare (popmax 0.0571%, sas) (gnomAD).

What do computational predictors say about TRDN p.Val66Ile (c.196G>A)?

AlphaMissense predicts likely benign (score 0.1732) — an in-silico prediction, not a clinical call.

TRDN p.Val66Ile

c.196G>A · rs372169818 · VCV463674

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1732 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0571%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.1732	likely benign
REVEL	0.267	benign-leaning
SaProt	LLR -8.37	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 4.8	GERP 2, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 418 kb · p 0.011 · regional, not allelic
Overall
CADD	24.6	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 0.0571% South Asian · 52/91,086 alleles

Filtering AF 0.0447% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0403%

Overall 0.00514% 83/1,613,846 alleles · ultra-rare exomes 73/1,461,668 · genomes 10/152,178 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0571%	1,752
Admixed American	0.02%	5,001
African / African-American	0.012%	8,333
Remaining individualsnot grpmax-eligible	0.0048%	20,829
European (non-Finnish)	0.000593%	168,549

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.Val66Ile
Coding: c.196G>A
MANE Select: NM_006073
dbSNP: rs372169818
Type: single nucleotide variant
Location: chr6:123570959 (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

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

Also linked: catecholaminergic polymorphic ventricular tachycardia 1

Similar variants

TRDN p.Val66Phe 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-val66ile (accessed [today's date]).

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