Is THBD p.Pro459Ser (c.1375C>T) pathogenic?

THBD p.Pro459Ser (c.1375C>T) is classified Uncertain significance in THBD (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-03-10). AlphaMissense: ambiguous (0.4172); Absent from gnomAD v4.1; Associated with thrombomodulin-related bleeding disorder.

What condition is associated with THBD p.Pro459Ser (c.1375C>T)?

THBD p.Pro459Ser (c.1375C>T) is associated with thrombomodulin-related bleeding disorder, atypical hemolytic-uremic syndrome with thrombomodulin anomaly (ClinVar).

How common is THBD p.Pro459Ser (c.1375C>T) in the general population?

THBD p.Pro459Ser (c.1375C>T) is absent from gnomAD v4.1 (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.Pro459Ser (c.1375C>T)?

AlphaMissense predicts ambiguous (score 0.4172) — an in-silico prediction, not a clinical call.

THBD p.Pro459Ser

c.1375C>T · rs2515203147 · VCV1721565

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4172 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

thrombomodulin-related bleeding disorder

Computational evidence

Protein change
AlphaMissense	0.4172	ambiguous
REVEL	0.331	indeterminate
SaProt	LLR -13.46	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.5	GERP 1.4, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 1,724 bp · p 0.25 · regional, not allelic
Overall
CADD	22.5	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: THBD
Protein: p.Pro459Ser
Coding: c.1375C>T
MANE Select: NM_000361
dbSNP: rs2515203147
Type: single nucleotide variant
Location: chr20:23048130 (GRCh38)
Gene constraint: LOEUF 1.938 · pLI 0.05 (gnomAD)
Structure: AlphaFold pLDDT 79.35 · 13 PDB
Residue 459: the egf-like 6; calcium-binding 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

Similar variants

THBD p.Pro459Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
THBD p.Pro459= Likely benign ★ 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

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-pro459ser (accessed [today's date]).

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