Is CFH p.Lys474fs (c.1422del) pathogenic?

CFH p.Lys474fs (c.1422del) is classified Pathogenic in CFH (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-02). Associated with atypical hemolytic-uremic syndrome.

What condition is associated with CFH p.Lys474fs (c.1422del)?

CFH p.Lys474fs (c.1422del) is associated with atypical hemolytic-uremic syndrome (ClinVar).

How is Atypical hemolytic uremic syndrome inherited?

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

CFH p.Lys474fs

c.1422del · VCV4291391

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

Conditions

atypical hemolytic-uremic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a LoF-intolerant gene
NMD	predicted	premature termination codon in exon 10 of 22
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.11	GERP -3.5
Region caveats
Repeat context	seg dup	· reads may not map uniquely · confidence, not pathogenicity

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Variant & gene context

Gene: CFH
Protein: p.Lys474fs
Coding: c.1422del
MANE Select: NM_000186
Type: Deletion
Location: chr1:196713818 (GRCh38)
Gene constraint: LOEUF 0.43 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 78.54 · 51 PDB
Residue 474: a β-strand; a disulfide bond; the sushi 8 domain

Full CFH 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

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

CFH p.Ala415fs Pathogenic ★★ same condition
CFH p.Phe960fs Pathogenic/Likely pathogenic ★★ same condition
CFH p.Leu750_Lys751del Uncertain significance ★★ same condition
CFH c.350+1del Pathogenic ★ same condition
CFH p.Arg885fs Pathogenic ★ same condition
CFH p.Asp748fs Pathogenic ★ same condition
CFH p.Cys16fs Likely pathogenic ★ same condition
CFH p.Lys1162fs Pathogenic ★ 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/cfh-p-lys474fs (accessed [today's date]).

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