Is THBD p.Val81Ile (c.241G>A) pathogenic?

THBD p.Val81Ile (c.241G>A) is classified Uncertain significance in THBD (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-07). AlphaMissense: likely benign (0.0839); Ultra-rare (popmax 0.02%, mid); Associated with thrombomodulin-related bleeding disorder.

What condition is associated with THBD p.Val81Ile (c.241G>A)?

THBD p.Val81Ile (c.241G>A) is associated with thrombomodulin-related bleeding disorder, atypical hemolytic-uremic syndrome with thrombomodulin anomaly (ClinVar).

How common is THBD p.Val81Ile (c.241G>A) in the general population?

THBD p.Val81Ile (c.241G>A) is ultra-rare (popmax 0.02%, mid) (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.Val81Ile (c.241G>A)?

AlphaMissense predicts likely benign (score 0.0839) — an in-silico prediction, not a clinical call.

THBD p.Val81Ile

c.241G>A · rs772288987 · VCV1358168

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0839 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.02%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

thrombomodulin-related bleeding disorder

Computational evidence

Protein change
AlphaMissense	0.0839	likely benign
REVEL	0.459	indeterminate
SaProt	LLR -8.11	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.59	GERP -2.4, phastCons 0.015
Regional constraint	o/e 1.04	unconstrained · MANE · 1,724 bp · p 0.25 · regional, not allelic
Overall
CADD	1.605	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.02% Middle Eastern · 1/4,992 alleles

Filtering AF 0.00235% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00147%

Overall 0.00129% 20/1,546,220 alleles · ultra-rare exomes 19/1,394,532 · genomes 1/151,688 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.02%	4,992
South Asian	0.006%	16,674
African / African-American	0.00552%	18,128
Remaining individualsnot grpmax-eligible	0.00167%	59,888
European (non-Finnish)	0.000783%	127,638

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.Val81Ile
Coding: c.241G>A
MANE Select: NM_000361
dbSNP: rs772288987
Type: single nucleotide variant
Location: chr20:23049264 (GRCh38)
Gene constraint: LOEUF 1.938 · pLI 0.05 (gnomAD)
Structure: AlphaFold pLDDT 79.35 · 13 PDB
Residue 81: 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; 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

Also linked: atypical hemolytic-uremic syndrome with thrombomodulin anomaly

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-val81ile (accessed [today's date]).

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