Is THBD p.Pro508Leu (c.1523C>T) pathogenic?

THBD p.Pro508Leu (c.1523C>T) is classified Conflicting classifications of pathogenicity in THBD (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-09-17). AlphaMissense: likely benign (0.1098); Very rare (popmax 0.00886%, sas); Associated with thrombomodulin-related bleeding disorder.

What condition is associated with THBD p.Pro508Leu (c.1523C>T)?

THBD p.Pro508Leu (c.1523C>T) is associated with thrombomodulin-related bleeding disorder (ClinVar).

How common is THBD p.Pro508Leu (c.1523C>T) in the general population?

THBD p.Pro508Leu (c.1523C>T) is very rare (popmax 0.00886%, sas) (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.Pro508Leu (c.1523C>T)?

AlphaMissense predicts likely benign (score 0.1098) — an in-silico prediction, not a clinical call.

THBD p.Pro508Leu

c.1523C>T · rs201936427 · VCV1684336

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1098 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00886%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

thrombomodulin-related bleeding disorder

Computational evidence

Protein change
AlphaMissense	0.1098	likely benign
REVEL	0.236	benign-leaning
SaProt	LLR -7.61	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.8	GERP -0.38, phastCons 0.98
Regional constraint	o/e 1.04	unconstrained · MANE · 1,724 bp · p 0.25 · regional, not allelic
Overall
CADD	17.74	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 0.00886% South Asian · 8/90,324 alleles

Filtering AF 0.0044% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00314%

Overall 0.00889% 143/1,608,272 alleles · very rare exomes 130/1,455,900 · genomes 13/152,372 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.145%	691
Remaining individualsnot grpmax-eligible	0.0145%	6,918
South Asiangrpmax	0.00886%	11,291
European (non-Finnish)	0.00289%	34,637
Admixed American	0.00169%	59,152

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro508Leu
Coding: c.1523C>T
MANE Select: NM_000361
dbSNP: rs201936427
Type: single nucleotide variant
Location: chr20:23047982 (GRCh38)
Gene constraint: LOEUF 1.938 · pLI 0.05 (gnomAD)
Structure: AlphaFold pLDDT 79.35 · 13 PDB
Residue 508: the 'involved in alpha-l/beta-2 and alpha-m/beta-2 integrin binding' region

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.Pro508Ala Uncertain significance ★ ⚠ same residue
THBD p.Pro508Gln 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

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-pro508leu (accessed [today's date]).

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