Is THBD p.Glu181= (c.543G>A) pathogenic?

THBD p.Glu181= (c.543G>A) is classified Benign/Likely benign in THBD (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-22). Rare (popmax 0.177%, sas); Associated with thrombomodulin-related bleeding disorder.

What condition is associated with THBD p.Glu181= (c.543G>A)?

THBD p.Glu181= (c.543G>A) is associated with thrombomodulin-related bleeding disorder, atypical hemolytic-uremic syndrome with thrombomodulin anomaly (ClinVar).

How common is THBD p.Glu181= (c.543G>A) in the general population?

THBD p.Glu181= (c.543G>A) is rare (popmax 0.177%, sas) (gnomAD).

How is Thrombomodulin-related bleeding disorder inherited?

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

THBD p.Glu181=

c.543G>A · rs542108654 · VCV897136

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

rare (popmax 0.177%, sas)

Conditions

thrombomodulin-related bleeding disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.32	GERP -3.1
Overall
CADD	3.993	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.177% South Asian · 151/85,370 alleles

Filtering AF 0.154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.145%

Overall 0.0124% 193/1,555,450 alleles · rare exomes 181/1,403,130 · genomes 12/152,320 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.177%	565
Remaining individualsnot grpmax-eligible	0.00829%	12,062
Admixed American	0.00372%	26,861
European (non-Finnish)	0.00303%	32,956

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.Glu181=
Coding: c.543G>A
MANE Select: NM_000361
dbSNP: rs542108654
Type: single nucleotide variant
Location: chr20:23048962 (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

Also linked: atypical hemolytic-uremic syndrome with thrombomodulin anomaly

For Thrombomodulin-related bleeding disorder (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages

Similar variants

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THBD p.Ala271Thr Uncertain significance ★★ ⚠ same condition
THBD p.Ala284Gly Uncertain significance ★★ ⚠ same condition
THBD p.Ala395Val Uncertain significance ★★ ⚠ same condition
THBD p.Ala471Thr Uncertain significance ★★ ⚠ same condition
THBD p.Ala545Thr Uncertain significance ★★ ⚠ same condition
THBD p.Arg101Leu 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-glu181 (accessed [today's date]).

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