Is THBD p.Phe295= (c.885C>T) pathogenic?

THBD p.Phe295= (c.885C>T) is classified Uncertain significance in THBD (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-25). Very rare (popmax 0.000339%, nfe); Associated with atypical hemolytic-uremic syndrome with thrombomodulin anomaly.

What condition is associated with THBD p.Phe295= (c.885C>T)?

THBD p.Phe295= (c.885C>T) is associated with atypical hemolytic-uremic syndrome with thrombomodulin anomaly (ClinVar).

How common is THBD p.Phe295= (c.885C>T) in the general population?

THBD p.Phe295= (c.885C>T) is very rare (popmax 0.000339%, nfe) (gnomAD).

THBD p.Phe295=

c.885C>T · rs1568666169 · VCV896686

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

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 0.22	GERP -3.2, phastCons 0.37
Overall
CADD	6.884	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000339% European (non-Finnish) · 4/1,179,348 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.00025% 4/1,597,892 alleles · very rare exomes 4/1,445,520 · genomes 0/152,372 · 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.Phe295=
Coding: c.885C>T
MANE Select: NM_000361
dbSNP: rs1568666169
Type: single nucleotide variant
Location: chr20:23048620 (GRCh38)
Gene constraint: LOEUF 1.938 · pLI 0.05 (gnomAD)
Structure: AlphaFold pLDDT 79.35 · 13 PDB
Residue 295: the egf-like 2 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.Phe295Cys 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
THBD p.Arg101Leu Uncertain significance ★★ ⚠ same condition
THBD p.Arg315Leu 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-phe295 (accessed [today's date]).

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