Is TRDN p.Lys528Arg (c.1583A>G) pathogenic?

TRDN p.Lys528Arg (c.1583A>G) is classified Likely benign in TRDN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-13). AlphaMissense: likely benign (0.1086); Ultra-rare (popmax 0.0311%, sas); Associated with Cardiovascular phenotype.

What condition is associated with TRDN p.Lys528Arg (c.1583A>G)?

TRDN p.Lys528Arg (c.1583A>G) is associated with Cardiovascular phenotype (ClinVar).

How common is TRDN p.Lys528Arg (c.1583A>G) in the general population?

TRDN p.Lys528Arg (c.1583A>G) is ultra-rare (popmax 0.0311%, sas) (gnomAD).

What do computational predictors say about TRDN p.Lys528Arg (c.1583A>G)?

AlphaMissense predicts likely benign (score 0.1086) — an in-silico prediction, not a clinical call.

TRDN p.Lys528Arg

c.1583A>G · rs771471056 · VCV2621397

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1086 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0311%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.1086	likely benign
REVEL	0.015	strongly benign-leaning
SaProt	LLR -9.19	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>A here scores Δ0.39 · evaluated, not missing
Constraint at this position
Conservation	phyloP 1.3	GERP -0.72, phastCons 0.94
Regional constraint	o/e 1.09	unconstrained · MANE · 418 kb · p 0.011 · regional, not allelic
Overall
CADD	20.8	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 0.0311% South Asian · 28/90,144 alleles

Filtering AF 0.022% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.019%

Overall 0.00174% 28/1,608,678 alleles · ultra-rare exomes 27/1,456,530 · genomes 1/152,148 · joint denominator

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.Lys528Arg
Coding: c.1583A>G
MANE Select: NM_006073
dbSNP: rs771471056
Type: single nucleotide variant
Location: chr6:123274655 (GRCh38)
Gene constraint: LOEUF 1.359 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 47.65
Residue 528: 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

Similar variants

TRDN p.Lys528Glu Uncertain significance ★★ ⚠ same residue
TRDN p.Lys528= Likely benign ★ same residue
TRDN p.Glu168Ter Pathogenic/Likely pathogenic ★★ same condition
TRDN p.Lys177Ter Pathogenic ★★ same condition
TRDN c.1166-2A>C Uncertain significance ★★ same condition
TRDN c.1273+4T>C Uncertain significance ★★ same condition
TRDN c.1273+5G>A Uncertain significance ★★ same condition
TRDN c.1322-10T>A Uncertain significance ★★ 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-lys528arg (accessed [today's date]).

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