Is THBD p.Pro501Leu (c.1502C>T) pathogenic?

THBD p.Pro501Leu (c.1502C>T) is classified Benign/Likely benign in THBD (ClinVar, Multiple submitters, 13 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.092); Rare (popmax 0.33%, nfe); Associated with atypical hemolytic-uremic syndrome.

What condition is associated with THBD p.Pro501Leu (c.1502C>T)?

THBD p.Pro501Leu (c.1502C>T) is associated with atypical hemolytic-uremic syndrome, thrombocytopenia, atypical hemolytic-uremic syndrome with thrombomodulin anomaly (ClinVar).

How common is THBD p.Pro501Leu (c.1502C>T) in the general population?

THBD p.Pro501Leu (c.1502C>T) is rare (popmax 0.33%, nfe) (gnomAD).

How is Atypical hemolytic uremic syndrome inherited?

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

What do computational predictors say about THBD p.Pro501Leu (c.1502C>T)?

AlphaMissense predicts likely benign (score 0.092) — an in-silico prediction, not a clinical call.

THBD p.Pro501Leu

c.1502C>T · rs1800579 · VCV337882

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 13 submitters

AlphaMissense

likely benign

0.092 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.33%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

atypical hemolytic-uremic syndrome

Computational evidence

Protein change
AlphaMissense	0.092	likely benign
REVEL	0.261	benign-leaning
SaProt	LLR -7.68	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 9.7	GERP 1.4, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 1,724 bp · p 0.25 · regional, not allelic
Overall
CADD	21.7	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 0.33% European (non-Finnish) · 3,887/1,177,858 alleles

Filtering AF 0.321% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.318%

Overall 0.268% 4,304/1,608,780 alleles · rare exomes 4,010/1,456,422 · genomes 294/152,358 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.33%	303
Ashkenazi Jewishnot grpmax-eligible	0.187%	535
Remaining individualsnot grpmax-eligible	0.174%	576
Admixed American	0.148%	674
Finnishnot grpmax-eligible	0.127%	786
Middle Eastern	0.0661%	1,513
South Asian	0.0652%	1,533
African / African-American	0.0307%	3,260

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.Pro501Leu
Coding: c.1502C>T
MANE Select: NM_000361
dbSNP: rs1800579
Type: single nucleotide variant
Location: chr20:23048003 (GRCh38)
Gene constraint: LOEUF 1.938 · pLI 0.05 (gnomAD)
Structure: AlphaFold pLDDT 79.35 · 13 PDB
Residue 501: the 'involved in alpha-l/beta-2 and alpha-m/beta-2 integrin binding' region; the 'disordered' region; a UniProt-annotated variant site (in ahus6; cells transfected with the mutant are less effective in converting c3b to ic3b on the cell surface after complement activation)

Full THBD gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

atypical hemolytic-uremic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: thrombocytopenia atypical hemolytic-uremic syndrome with thrombomodulin anomaly thrombomodulin-related bleeding disorder

For Atypical hemolytic uremic syndrome (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Not applicable
Onset: All ages
Prevalence: 1-9 / 1 000 000 (United States)

Similar variants

THBD p.Pro501= Likely benign ★★ same residue
THBD p.Cys537Ter Pathogenic/Likely pathogenic ★★ same condition
THBD p.Ala139Ser Uncertain significance ★★ ⚠ same condition
THBD p.Ala255Pro 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-pro501leu (accessed [today's date]).

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