Is THBD p.Pro496fs (c.1487del) pathogenic?

THBD p.Pro496fs (c.1487del) is classified Likely pathogenic in THBD (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-22). Very rare (popmax 0.000255%, nfe); Associated with thrombomodulin-related bleeding disorder.

What condition is associated with THBD p.Pro496fs (c.1487del)?

THBD p.Pro496fs (c.1487del) is associated with thrombomodulin-related bleeding disorder (ClinVar).

How common is THBD p.Pro496fs (c.1487del) in the general population?

THBD p.Pro496fs (c.1487del) is very rare (popmax 0.000255%, nfe) (gnomAD).

How is Thrombomodulin-related bleeding disorder inherited?

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

THBD p.Pro496fs

c.1487del · rs1600409323 · VCV627170

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000255%, nfe)

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 -20	GERP -2.7

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000255% European (non-Finnish) · 3/1,178,138 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,609,416 alleles · very rare exomes 3/1,457,082 · genomes 0/152,334 · 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: THBD
Protein: p.Pro496fs
Coding: c.1487del
MANE Select: NM_000361
dbSNP: rs1600409323
Type: Deletion
Location: chr20:23048018 (GRCh38)
Gene constraint: LOEUF 1.938 · pLI 0.05 (gnomAD)
Structure: AlphaFold pLDDT 79.35 · 13 PDB
Residue 496: the 'involved in alpha-l/beta-2 and alpha-m/beta-2 integrin binding' region; the 'disordered' region

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

Similar variants

THBD p.Ala43fs 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.Pro496= Uncertain significance ★ same residue
THBD p.Tyr306del Uncertain significance ★ same condition
THBD c.*23_*40del Likely benign ★ 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-pro496fs (accessed [today's date]).

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