Is THBD p.Gln564fs (c.1688dup) pathogenic?

THBD p.Gln564fs (c.1688dup) is classified Uncertain significance in THBD (ClinVar, Single submitter, 2 submitters; last evaluated 2025-09-22). Very rare (popmax 0.000171%, nfe); Associated with thrombomodulin-related bleeding disorder.

What condition is associated with THBD p.Gln564fs (c.1688dup)?

THBD p.Gln564fs (c.1688dup) is associated with thrombomodulin-related bleeding disorder (ClinVar).

How common is THBD p.Gln564fs (c.1688dup) in the general population?

THBD p.Gln564fs (c.1688dup) is very rare (popmax 0.000171%, 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.Gln564fs

c.1688dup · rs2515202194 · VCV12716

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000171%, 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 2.3	GERP -0.57, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000171% European (non-Finnish) · 2/1,173,008 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000125% 2/1,598,392 alleles · very rare exomes 2/1,445,994 · genomes 0/152,398 · 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.Gln564fs
Coding: c.1688dup
MANE Select: NM_000361
dbSNP: rs2515202194
Type: Duplication
Location: chr20:23047816 (GRCh38)
Gene constraint: LOEUF 1.938 · pLI 0.05 (gnomAD)
Structure: AlphaFold pLDDT 79.35 · 13 PDB

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-gln564fs (accessed [today's date]).

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