Is THBD p.Asp434Ala (c.1301A>C) pathogenic?

THBD p.Asp434Ala (c.1301A>C) is classified Uncertain significance in THBD (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-22). AlphaMissense: ambiguous (0.497); Absent from gnomAD v4.1; Associated with thrombomodulin-related bleeding disorder.

What condition is associated with THBD p.Asp434Ala (c.1301A>C)?

THBD p.Asp434Ala (c.1301A>C) is associated with thrombomodulin-related bleeding disorder (ClinVar).

How common is THBD p.Asp434Ala (c.1301A>C) in the general population?

THBD p.Asp434Ala (c.1301A>C) is absent from gnomAD v4.1 (gnomAD).

How is Thrombomodulin-related bleeding disorder inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about THBD p.Asp434Ala (c.1301A>C)?

AlphaMissense predicts ambiguous (score 0.497) — an in-silico prediction, not a clinical call.

THBD p.Asp434Ala

c.1301A>C · VCV4280437

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.497 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

thrombomodulin-related bleeding disorder

Computational evidence

Protein change
AlphaMissense	0.497	ambiguous
REVEL	0.56	indeterminate
SaProt	LLR -5.55	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.4, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 1,724 bp · p 0.25 · regional, not allelic
Overall
CADD	25.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: THBD
Protein: p.Asp434Ala
Coding: c.1301A>C
MANE Select: NM_000361
Type: single nucleotide variant
Location: chr20:23048204 (GRCh38)
Gene constraint: LOEUF 1.938 · pLI 0.05 (gnomAD)
Structure: AlphaFold pLDDT 79.35 · 13 PDB
Residue 434: the egf-like 5 domain; a β-strand

Full THBD gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

thrombomodulin-related bleeding disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Thrombomodulin-related bleeding disorder (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages

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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/thbd-p-asp434ala (accessed [today's date]).

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