Is THBD p.Pro196Arg (c.587C>G) pathogenic?

THBD p.Pro196Arg (c.587C>G) is classified Uncertain significance in THBD (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-04). AlphaMissense: ambiguous (0.5457); Very rare (popmax 0.00398%, amr); Associated with thrombomodulin-related bleeding disorder.

What condition is associated with THBD p.Pro196Arg (c.587C>G)?

THBD p.Pro196Arg (c.587C>G) is associated with thrombomodulin-related bleeding disorder, atypical hemolytic-uremic syndrome with thrombomodulin anomaly (ClinVar).

How common is THBD p.Pro196Arg (c.587C>G) in the general population?

THBD p.Pro196Arg (c.587C>G) is very rare (popmax 0.00398%, 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.Pro196Arg (c.587C>G)?

AlphaMissense predicts ambiguous (score 0.5457) — an in-silico prediction, not a clinical call.

THBD p.Pro196Arg

c.587C>G · VCV3587132

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5457 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00398%, amr)

Conditions

thrombomodulin-related bleeding disorder

Computational evidence

Protein change
AlphaMissense	0.5457	ambiguous
REVEL	0.603	indeterminate
SaProt	LLR -10.61	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.6	GERP 0.69, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 1,724 bp · p 0.25 · regional, not allelic
Overall
CADD	26.6	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 0.00398% Admixed American · 2/50,202 alleles

Filtering AF 0.000661% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000247%

Overall 0.000196% 3/1,527,920 alleles · very rare exomes 3/1,375,590 · genomes 0/152,330 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00398%	25,101
European (non-Finnish)	8.77e-05%	1,140,029

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.Pro196Arg
Coding: c.587C>G
MANE Select: NM_000361
Type: single nucleotide variant
Location: chr20:23048918 (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

THBD p.Pro196= Uncertain significance ★ same residue
THBD p.Pro196Leu Uncertain significance ★ same residue
THBD p.Pro196Ser 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

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-pro196arg (accessed [today's date]).

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