Is THBD p.Pro396Arg (c.1187C>G) pathogenic?

THBD p.Pro396Arg (c.1187C>G) is classified Uncertain significance in THBD (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-22). AlphaMissense: likely benign (0.2583); Ultra-rare (popmax 0.0223%, eas); Associated with thrombomodulin-related bleeding disorder.

What condition is associated with THBD p.Pro396Arg (c.1187C>G)?

THBD p.Pro396Arg (c.1187C>G) is associated with thrombomodulin-related bleeding disorder (ClinVar).

How common is THBD p.Pro396Arg (c.1187C>G) in the general population?

THBD p.Pro396Arg (c.1187C>G) is ultra-rare (popmax 0.0223%, 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.Pro396Arg (c.1187C>G)?

AlphaMissense predicts likely benign (score 0.2583) — an in-silico prediction, not a clinical call.

THBD p.Pro396Arg

c.1187C>G · rs761493124 · VCV2695700

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2583 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0223%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

thrombomodulin-related bleeding disorder

Computational evidence

Protein change
AlphaMissense	0.2583	likely benign
REVEL	0.288	benign-leaning
SaProt	LLR -11.22	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP 1.4, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 1,724 bp · p 0.25 · regional, not allelic
Overall
CADD	22.2	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 0.0223% East Asian · 10/44,880 alleles

Filtering AF 0.012% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00916%

Overall 0.00062% 10/1,613,906 alleles · ultra-rare exomes 10/1,461,562 · genomes 0/152,344 · 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.Pro396Arg
Coding: c.1187C>G
MANE Select: NM_000361
dbSNP: rs761493124
Type: single nucleotide variant
Location: chr20:23048318 (GRCh38)
Gene constraint: LOEUF 1.938 · pLI 0.05 (gnomAD)
Structure: AlphaFold pLDDT 79.35 · 13 PDB
Residue 396: a β-strand; the egf-like 4 domain

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

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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-pro396arg (accessed [today's date]).

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