Is THBD p.Pro353Thr (c.1057C>A) pathogenic?

THBD p.Pro353Thr (c.1057C>A) is classified Conflicting classifications of pathogenicity in THBD (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-09-22). AlphaMissense: likely benign (0.133); Ultra-rare (popmax 0.0245%, eas); Associated with atypical hemolytic-uremic syndrome.

What condition is associated with THBD p.Pro353Thr (c.1057C>A)?

THBD p.Pro353Thr (c.1057C>A) is associated with atypical hemolytic-uremic syndrome, thrombomodulin-related bleeding disorder (ClinVar).

How common is THBD p.Pro353Thr (c.1057C>A) in the general population?

THBD p.Pro353Thr (c.1057C>A) is ultra-rare (popmax 0.0245%, eas) (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.Pro353Thr (c.1057C>A)?

AlphaMissense predicts likely benign (score 0.133) — an in-silico prediction, not a clinical call.

THBD p.Pro353Thr

c.1057C>A · rs1300304839 · VCV1712464

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.133 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0245%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

atypical hemolytic-uremic syndrome

Computational evidence

Protein change
AlphaMissense	0.133	likely benign
REVEL	0.149	moderately benign-leaning
SaProt	LLR -8.52	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 -0.12	GERP -2.8
Regional constraint	o/e 1.04	unconstrained · MANE · 1,724 bp · p 0.25 · regional, not allelic
Overall
CADD	0.771	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 0.0245% East Asian · 11/44,880 alleles

Filtering AF 0.0137% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0106%

Overall 0.000682% 11/1,613,552 alleles · ultra-rare exomes 9/1,461,342 · genomes 2/152,210 · 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.Pro353Thr
Coding: c.1057C>A
MANE Select: NM_000361
dbSNP: rs1300304839
Type: single nucleotide variant
Location: chr20:23048448 (GRCh38)
Gene constraint: LOEUF 1.938 · pLI 0.05 (gnomAD)
Structure: AlphaFold pLDDT 79.35 · 13 PDB
Residue 353: the egf-like 3; calcium-binding domain

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: 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.Pro353Ala Uncertain significance ★ ⚠ 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-pro353thr (accessed [today's date]).

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