Is CFHR5 p.Asp409fs (c.1225del) pathogenic?

CFHR5 p.Asp409fs (c.1225del) is classified Uncertain significance in CFHR5 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-04-11). Ultra-rare (popmax 0.013%, nfe); Associated with CFHR5 deficiency.

What condition is associated with CFHR5 p.Asp409fs (c.1225del)?

CFHR5 p.Asp409fs (c.1225del) is associated with CFHR5 deficiency (ClinVar).

How common is CFHR5 p.Asp409fs (c.1225del) in the general population?

CFHR5 p.Asp409fs (c.1225del) is ultra-rare (popmax 0.013%, nfe) (gnomAD).

CFHR5 p.Asp409fs

c.1225del · rs771972507 · VCV632093

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.013%, nfe)

Conditions

CFHR5 deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 8 of 10
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.36	GERP -0.74
Overall
CADD	21.9	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.013% European (non-Finnish) · 153/1,179,608 alleles

Filtering AF 0.0113% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0107%

Overall 0.00979% 158/1,613,424 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.013%	7,710
Remaining individualsnot grpmax-eligible	0.00641%	15,611
African / African-American	0.00134%	74,884

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: CFHR5
Protein: p.Asp409fs
Coding: c.1225del
MANE Select: NM_030787
dbSNP: rs771972507
Type: Deletion
Location: chr1:197002558 (GRCh38)
Gene constraint: LOEUF 1.466 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.76
Residue 409: a disulfide bond; the sushi 7 domain

Full CFHR5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

CFHR5 deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CFHR5 p.Glu226fs Conflicting classifications of pathogenicity ★ same condition
CFHR5 c.608-3T>A Uncertain significance ★★ same condition
CFHR5 p.Arg441Cys Uncertain significance ★★ ⚠ same condition
CFHR5 p.Asn216Phe Uncertain significance ★★ same condition
CFHR5 p.Gln399Ter Uncertain significance ★★ same condition
CFHR5 p.Ile222Thr Uncertain significance ★★ ⚠ same condition
CFHR5 p.Met1Val Uncertain significance ★★ same condition
CFHR5 p.Ser195Thr 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/cfhr5-p-asp409fs (accessed [today's date]).

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