Is THBD p.Ala43fs (c.127del) pathogenic?

THBD p.Ala43fs (c.127del) is classified Likely pathogenic in THBD (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-15). Associated with thrombomodulin-related bleeding disorder.

What condition is associated with THBD p.Ala43fs (c.127del)?

THBD p.Ala43fs (c.127del) is associated with thrombomodulin-related bleeding disorder, atypical hemolytic-uremic syndrome with thrombomodulin anomaly (ClinVar).

How is Thrombomodulin-related bleeding disorder inherited?

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

THBD p.Ala43fs

c.127del · VCV3587142

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

Conditions

thrombomodulin-related bleeding disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (1 of 1) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.2	GERP -2.5, phastCons 0.001

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Variant & gene context

Gene: THBD
Protein: p.Ala43fs
Coding: c.127del
MANE Select: NM_000361
Type: Deletion
Location: chr20:23049378 (GRCh38)
Gene constraint: LOEUF 1.938 · pLI 0.05 (gnomAD)
Structure: AlphaFold pLDDT 79.35 · 13 PDB
Residue 43: a UniProt-annotated variant site (in ahus6; cells transfected with the mutant are less effective in converting c3b to ic3b on the cell surface after complement activation); the c-type lectin domain

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

Also linked: atypical hemolytic-uremic syndrome with thrombomodulin anomaly

For Thrombomodulin-related bleeding disorder (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages

Similar variants

THBD p.Ala43= Likely benign ★★ same residue
THBD p.Ala43Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
THBD p.Pro496fs Likely pathogenic ★★ same condition
THBD p.Val454fs Likely pathogenic ★ same condition
THBD p.Arg264fs Uncertain significance ★ same condition
THBD p.Asp418fs Uncertain significance ★ same condition
THBD p.Gly82fs Conflicting classifications of pathogenicity ★ same condition
THBD p.Tyr306del 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/thbd-p-ala43fs (accessed [today's date]).

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