Is THBD p.Phe197= (c.591C>T) pathogenic?

THBD p.Phe197= (c.591C>T) is classified Likely benign in THBD (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-22). Very rare (popmax 0.00239%, sas); Associated with thrombomodulin-related bleeding disorder.

What condition is associated with THBD p.Phe197= (c.591C>T)?

THBD p.Phe197= (c.591C>T) is associated with thrombomodulin-related bleeding disorder (ClinVar).

How common is THBD p.Phe197= (c.591C>T) in the general population?

THBD p.Phe197= (c.591C>T) is very rare (popmax 0.00239%, sas) (gnomAD).

How is Thrombomodulin-related bleeding disorder inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

THBD p.Phe197=

c.591C>T · rs1377394971 · VCV2170486

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00239%, sas)

Conditions

thrombomodulin-related bleeding disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.29	GERP -3.1, phastCons 0.013
Overall
CADD	7.125	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00239% South Asian · 2/83,594 alleles

Filtering AF 0.000397% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000164%

Overall 0.00059% 9/1,526,134 alleles · very rare exomes 7/1,373,948 · genomes 2/152,186 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00239%	41,797
European (non-Finnish)	0.000614%	162,775

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.Phe197=
Coding: c.591C>T
MANE Select: NM_000361
dbSNP: rs1377394971
Type: single nucleotide variant
Location: chr20:23048914 (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.Phe197Val 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-phe197 (accessed [today's date]).

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