Is THBD p.Tyr39Phe (c.116A>T) pathogenic?

THBD p.Tyr39Phe (c.116A>T) is classified Conflicting classifications of pathogenicity in THBD (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.064); Ultra-rare (popmax 0.0376%, amr); Associated with thrombomodulin-related bleeding disorder.

What condition is associated with THBD p.Tyr39Phe (c.116A>T)?

THBD p.Tyr39Phe (c.116A>T) is associated with thrombomodulin-related bleeding disorder, atypical hemolytic-uremic syndrome with thrombomodulin anomaly (ClinVar).

How common is THBD p.Tyr39Phe (c.116A>T) in the general population?

THBD p.Tyr39Phe (c.116A>T) is ultra-rare (popmax 0.0376%, amr) (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.Tyr39Phe (c.116A>T)?

AlphaMissense predicts likely benign (score 0.064) — an in-silico prediction, not a clinical call.

THBD p.Tyr39Phe

c.116A>T · rs776866172 · VCV1374247

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.064 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0376%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

thrombomodulin-related bleeding disorder

Computational evidence

Protein change
AlphaMissense	0.064	likely benign
REVEL	0.12	moderately benign-leaning
SaProt	LLR -5.28	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 9	GERP 0.36, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 1,724 bp · p 0.25 · regional, not allelic
Overall
CADD	10.02	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 0.0376% Admixed American · 22/58,442 alleles

Filtering AF 0.0255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0214%

Overall 0.00244% 39/1,599,204 alleles · ultra-rare exomes 35/1,447,174 · genomes 4/152,030 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0376%	2,656
Remaining individualsnot grpmax-eligible	0.00969%	10,320
African / African-American	0.00134%	74,712
European (non-Finnish)	0.000852%	117,407

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.Tyr39Phe
Coding: c.116A>T
MANE Select: NM_000361
dbSNP: rs776866172
Type: single nucleotide variant
Location: chr20:23049389 (GRCh38)
Gene constraint: LOEUF 1.938 · pLI 0.05 (gnomAD)
Structure: AlphaFold pLDDT 79.35 · 13 PDB
Residue 39: 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-tyr39phe (accessed [today's date]).

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