Is THBD p.Pro94= (c.282C>G) pathogenic?

THBD p.Pro94= (c.282C>G) is classified Conflicting classifications of pathogenicity in THBD (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-12-01). Ultra-rare (popmax 0.0549%, mid); Associated with atypical hemolytic-uremic syndrome with thrombomodulin anomaly.

What condition is associated with THBD p.Pro94= (c.282C>G)?

THBD p.Pro94= (c.282C>G) is associated with atypical hemolytic-uremic syndrome with thrombomodulin anomaly (ClinVar).

How common is THBD p.Pro94= (c.282C>G) in the general population?

THBD p.Pro94= (c.282C>G) is ultra-rare (popmax 0.0549%, mid) (gnomAD).

THBD p.Pro94=

c.282C>G · rs538290084 · VCV809234

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0549%, mid)

Conditions

atypical hemolytic-uremic syndrome with thrombomodulin anomaly

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 -3.2	GERP -3.4
Overall
CADD	1.083	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0549% Middle Eastern · 3/5,460 alleles

Filtering AF 0.0283% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0237%

Overall 0.0185% 282/1,524,152 alleles · ultra-rare exomes 251/1,376,586 · genomes 31/147,566 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0549%	1,820
Admixed American	0.0422%	2,371
European (non-Finnish)	0.0211%	4,733
Remaining individualsnot grpmax-eligible	0.0172%	5,813
African / African-American	0.00558%	17,924
Finnishnot grpmax-eligible	0.0053%	18,882
Ashkenazi Jewishnot grpmax-eligible	0.00367%	27,262
South Asian	0.00119%	83,772

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.Pro94=
Coding: c.282C>G
MANE Select: NM_000361
dbSNP: rs538290084
Type: single nucleotide variant
Location: chr20:23049223 (GRCh38)
Gene constraint: LOEUF 1.938 · pLI 0.05 (gnomAD)
Structure: AlphaFold pLDDT 79.35 · 13 PDB
Residue 94: the c-type lectin domain

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

Disease context

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

Similar variants

THBD p.Pro94Ala Uncertain significance ★ ⚠ same residue
THBD p.Pro94Leu Uncertain significance ★ ⚠ same residue
THBD p.Pro94Ser Uncertain significance ★ ⚠ same residue
THBD p.Ala139Ser 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-pro94 (accessed [today's date]).

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