Is THBD p.Ala239Val (c.716C>T) pathogenic?

THBD p.Ala239Val (c.716C>T) is classified Conflicting classifications of pathogenicity in THBD (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2025-10-06). AlphaMissense: likely benign (0.089); Ultra-rare (popmax 0.0101%, nfe); Associated with thrombomodulin-related bleeding disorder.

What condition is associated with THBD p.Ala239Val (c.716C>T)?

THBD p.Ala239Val (c.716C>T) is associated with thrombomodulin-related bleeding disorder, thrombocytopenia, atypical hemolytic-uremic syndrome with thrombomodulin anomaly (ClinVar).

How common is THBD p.Ala239Val (c.716C>T) in the general population?

THBD p.Ala239Val (c.716C>T) is ultra-rare (popmax 0.0101%, nfe) (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.Ala239Val (c.716C>T)?

AlphaMissense predicts likely benign (score 0.089) — an in-silico prediction, not a clinical call.

THBD p.Ala239Val

c.716C>T · rs886056547 · VCV337890

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.089 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0101%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

thrombomodulin-related bleeding disorder

Computational evidence

Protein change
AlphaMissense	0.089	likely benign
REVEL	0.12	moderately benign-leaning
SaProt	LLR -4.89	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.34	GERP -2
Regional constraint	o/e 1.04	unconstrained · MANE · 1,724 bp · p 0.25 · regional, not allelic
Overall
CADD	3.822	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0101% European (non-Finnish) · 116/1,149,976 alleles

Filtering AF 0.00856% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00796%

Overall 0.00792% 122/1,540,246 alleles · ultra-rare exomes 117/1,388,052 · genomes 5/152,194 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0101%	9,914
Remaining individualsnot grpmax-eligible	0.005%	19,987
African / African-American	0.00409%	24,441

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.Ala239Val
Coding: c.716C>T
MANE Select: NM_000361
dbSNP: rs886056547
Type: single nucleotide variant
Location: chr20:23048789 (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: thrombocytopenia 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-ala239val (accessed [today's date]).

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