Is CFI p.Asp359Tyr (c.1075G>T) pathogenic?

CFI p.Asp359Tyr (c.1075G>T) is classified Uncertain significance in CFI (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-02). AlphaMissense: ambiguous (0.5347); Very rare (popmax 0.000763%, nfe); Associated with complement factor I deficiency.

What condition is associated with CFI p.Asp359Tyr (c.1075G>T)?

CFI p.Asp359Tyr (c.1075G>T) 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.Asp359Tyr (c.1075G>T) in the general population?

CFI p.Asp359Tyr (c.1075G>T) is very rare (popmax 0.000763%, nfe) (gnomAD).

How is Immunodeficiency with factor I anomaly inherited?

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

What do computational predictors say about CFI p.Asp359Tyr (c.1075G>T)?

AlphaMissense predicts ambiguous (score 0.5347) — an in-silico prediction, not a clinical call.

CFI p.Asp359Tyr

c.1075G>T · rs1000969873 · VCV2597062

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.5347 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000763%, nfe)

Conditions

complement factor I deficiency

Computational evidence

Protein change
AlphaMissense	0.5347	ambiguous
REVEL	0.436	indeterminate
SaProt	LLR -8.96	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.2	GERP -0.59, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 61 kb · p 0.95 · regional, not allelic
Overall
CADD	23.4	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 0.000763% European (non-Finnish) · 9/1,179,986 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000558% 9/1,614,026 alleles · very rare

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.Asp359Tyr
Coding: c.1075G>T
MANE Select: NM_000204
dbSNP: rs1000969873
Type: single nucleotide variant
Location: chr4:109749291 (GRCh38)
Gene constraint: LOEUF 1.076 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.50 · 2 PDB
Residue 359: a disulfide bond; the peptidase s1 domain; a β-strand

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

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-asp359tyr (accessed [today's date]).

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