Is CFI p.Glu180= (c.540A>G) pathogenic?

CFI p.Glu180= (c.540A>G) is classified Likely benign in CFI (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-09-26). Very rare (popmax 0.00167%, amr); Associated with complement factor I deficiency.

What condition is associated with CFI p.Glu180= (c.540A>G)?

CFI p.Glu180= (c.540A>G) is associated with complement factor I deficiency, atypical hemolytic-uremic syndrome with I factor anomaly, age related macular degeneration 13 (ClinVar).

How common is CFI p.Glu180= (c.540A>G) in the general population?

CFI p.Glu180= (c.540A>G) is very rare (popmax 0.00167%, amr) (gnomAD).

How is Immunodeficiency with factor I anomaly inherited?

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

CFI p.Glu180=

c.540A>G · rs759777516 · VCV347169

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Conditions

complement factor I deficiency

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 -1.5	GERP -3.2
Overall
CADD	3.755	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,026 alleles

Filtering AF 0.000542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.000868% 14/1,613,826 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,026
Remaining individualsnot grpmax-eligible	0.0016%	62,494
European (non-Finnish)	0.00102%	98,313

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: CFI
Protein: p.Glu180=
Coding: c.540A>G
MANE Select: NM_000204
dbSNP: rs759777516
Type: single nucleotide variant
Location: chr4:109761635 (GRCh38)
Gene constraint: LOEUF 1.076 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.50 · 2 PDB
Residue 180: a disulfide bond; the srcr domain

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

Disease context

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

Also linked: atypical hemolytic-uremic syndrome with I factor anomaly age related macular degeneration 13 atypical hemolytic-uremic syndrome

For Immunodeficiency with factor I anomaly (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood

Similar variants

CFI c.1429+1G>C Pathogenic/Likely pathogenic ★★ same condition
CFI c.57+1G>C Likely pathogenic ★★ same condition
CFI c.658+1G>A Likely pathogenic ★★ same condition
CFI c.905-1G>C Likely pathogenic ★★ same condition
CFI p.Ala258Thr Pathogenic/Likely pathogenic ★★ ⚠ same condition
CFI p.Arg187Ter Pathogenic/Likely pathogenic ★★ same condition
CFI p.Arg474Ter Pathogenic/Likely pathogenic ★★ same condition
CFI c.773-3C>T 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/cfi-p-glu180 (accessed [today's date]).

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