Is TRDN p.Lys556= (c.1668A>G) pathogenic?

TRDN p.Lys556= (c.1668A>G) is classified Uncertain significance in TRDN (ClinVar, Single submitter, 1 submitter; last evaluated 2019-11-19). Very rare (popmax 0.00375%, sas); Associated with Cardiovascular phenotype.

What condition is associated with TRDN p.Lys556= (c.1668A>G)?

TRDN p.Lys556= (c.1668A>G) is associated with Cardiovascular phenotype (ClinVar).

How common is TRDN p.Lys556= (c.1668A>G) in the general population?

TRDN p.Lys556= (c.1668A>G) is very rare (popmax 0.00375%, sas) (gnomAD).

TRDN p.Lys556=

c.1668A>G · rs1777253683 · VCV3076194

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00375%, sas)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.64	donor gain · deltas
Pangolin	Δ0.59	gain · loss 0.26 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 5.9	GERP 2, phastCons 1
Overall
CADD	20.8	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00375% South Asian · 3/79,960 alleles

Filtering AF 0.000996% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000476%

Overall 0.000327% 5/1,530,254 alleles · very rare exomes 5/1,378,108 · genomes 0/152,146 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00375%	26,653
European (non-Finnish)	0.000176%	569,256

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.Lys556=
Coding: c.1668A>G
MANE Select: NM_006073
dbSNP: rs1777253683
Type: single nucleotide variant
Location: chr6:123272968 (GRCh38)
Gene constraint: LOEUF 1.359 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 47.65
Residue 556: 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.Lys556Arg Uncertain significance ★ ⚠ 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
TRDN c.1537+1G>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-lys556 (accessed [today's date]).

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