Is THBD p.Phe17Leu (c.49T>C) pathogenic?

THBD p.Phe17Leu (c.49T>C) is classified Uncertain significance in THBD (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-07-31). AlphaMissense: likely benign (0.2868); Very rare (popmax 0.000956%, nfe); Associated with thrombomodulin-related bleeding disorder.

What condition is associated with THBD p.Phe17Leu (c.49T>C)?

THBD p.Phe17Leu (c.49T>C) is associated with thrombomodulin-related bleeding disorder, atypical hemolytic-uremic syndrome with thrombomodulin anomaly (ClinVar).

How common is THBD p.Phe17Leu (c.49T>C) in the general population?

THBD p.Phe17Leu (c.49T>C) is very rare (popmax 0.000956%, 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.Phe17Leu (c.49T>C)?

AlphaMissense predicts likely benign (score 0.2868) — an in-silico prediction, not a clinical call.

THBD p.Phe17Leu

c.49T>C · rs1600410618 · VCV636335

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2868 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000956%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

thrombomodulin-related bleeding disorder

Computational evidence

Protein change
AlphaMissense	0.2868	likely benign
REVEL	0.167	moderately benign-leaning
SaProt	LLR -3.33	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 0.76	GERP -3.5, phastCons 0.39
Regional constraint	o/e 1.04	unconstrained · MANE · 1,724 bp · p 0.25 · regional, not allelic
Overall
CADD	1.117	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 0.000956% European (non-Finnish) · 11/1,150,062 alleles

Filtering AF 0.000513% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000375%

Overall 0.000708% 11/1,553,098 alleles · very rare exomes 11/1,400,940 · genomes 0/152,158 · 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.Phe17Leu
Coding: c.49T>C
MANE Select: NM_000361
dbSNP: rs1600410618
Type: single nucleotide variant
Location: chr20:23049456 (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-phe17leu (accessed [today's date]).

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