Is TRDN p.Gln644Pro (c.1931A>C) pathogenic?

TRDN p.Gln644Pro (c.1931A>C) is classified Uncertain significance in TRDN (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-05). AlphaMissense: likely benign (0.0792); Ultra-rare (popmax 0.0131%, sas); Associated with Cardiovascular phenotype.

What condition is associated with TRDN p.Gln644Pro (c.1931A>C)?

TRDN p.Gln644Pro (c.1931A>C) is associated with Cardiovascular phenotype (ClinVar).

How common is TRDN p.Gln644Pro (c.1931A>C) in the general population?

TRDN p.Gln644Pro (c.1931A>C) is ultra-rare (popmax 0.0131%, sas) (gnomAD).

What do computational predictors say about TRDN p.Gln644Pro (c.1931A>C)?

AlphaMissense predicts likely benign (score 0.0792) — an in-silico prediction, not a clinical call.

TRDN p.Gln644Pro

c.1931A>C · rs769431351 · VCV3182073

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0792 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0131%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.0792	likely benign
REVEL	0.079	moderately benign-leaning
SaProt	LLR -4.30	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 2.7	GERP 0.11, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 418 kb · p 0.011 · regional, not allelic
Overall
CADD	20.9	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 0.0131% South Asian · 9/68,580 alleles

Filtering AF 0.00675% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00505%

Overall 0.000652% 9/1,379,326 alleles · ultra-rare exomes 7/1,227,252 · genomes 2/152,074 · 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.Gln644Pro
Coding: c.1931A>C
MANE Select: NM_006073
dbSNP: rs769431351
Type: single nucleotide variant
Location: chr6:123255101 (GRCh38)
Gene constraint: LOEUF 1.359 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 47.65
Residue 644: 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.Gln644= 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
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-gln644pro (accessed [today's date]).

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