Is THBD p.Leu2Phe (c.4C>T) pathogenic?

THBD p.Leu2Phe (c.4C>T) is classified Uncertain significance in THBD (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-22). AlphaMissense: likely benign (0.0839); Very rare (popmax 0.00993%, eas); Associated with thrombomodulin-related bleeding disorder.

What condition is associated with THBD p.Leu2Phe (c.4C>T)?

THBD p.Leu2Phe (c.4C>T) is associated with thrombomodulin-related bleeding disorder (ClinVar).

How common is THBD p.Leu2Phe (c.4C>T) in the general population?

THBD p.Leu2Phe (c.4C>T) is very rare (popmax 0.00993%, eas) (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.Leu2Phe (c.4C>T)?

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

THBD p.Leu2Phe

c.4C>T · rs1175683983 · VCV2146491

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0839 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00993%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

thrombomodulin-related bleeding disorder

Computational evidence

Protein change
AlphaMissense	0.0839	likely benign
REVEL	0.453	indeterminate
SaProt	LLR -9.21	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.2	GERP 1.7, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 1,724 bp · p 0.25 · regional, not allelic
Overall
CADD	22.2	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 0.00993% East Asian · 4/40,270 alleles

Filtering AF 0.00331% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00196%

Overall 0.000391% 6/1,535,148 alleles · very rare exomes 4/1,382,940 · genomes 2/152,208 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00993%	10,068
European (non-Finnish)	0.000175%	569,992

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.Leu2Phe
Coding: c.4C>T
MANE Select: NM_000361
dbSNP: rs1175683983
Type: single nucleotide variant
Location: chr20:23049501 (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

For Thrombomodulin-related bleeding disorder (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages

Similar variants

THBD p.Leu2Pro Uncertain significance ★ ⚠ same residue
THBD p.Cys537Ter Pathogenic/Likely pathogenic ★★ same condition
THBD p.Ala139Ser Uncertain significance ★★ ⚠ same condition
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

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-leu2phe (accessed [today's date]).

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