Is CFI p.Ile492Leu (c.1474A>C) pathogenic?

CFI p.Ile492Leu (c.1474A>C) is classified Uncertain significance in CFI (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-26). AlphaMissense: likely benign (0.0933); Very rare (popmax 0.00738%, nfe); Associated with age related macular degeneration 13.

What condition is associated with CFI p.Ile492Leu (c.1474A>C)?

CFI p.Ile492Leu (c.1474A>C) is associated with age related macular degeneration 13, complement factor I deficiency, atypical hemolytic-uremic syndrome with I factor anomaly (ClinVar).

How common is CFI p.Ile492Leu (c.1474A>C) in the general population?

CFI p.Ile492Leu (c.1474A>C) is very rare (popmax 0.00738%, nfe) (gnomAD).

What do computational predictors say about CFI p.Ile492Leu (c.1474A>C)?

AlphaMissense predicts likely benign (score 0.0933) — an in-silico prediction, not a clinical call.

CFI p.Ile492Leu

c.1474A>C · rs200025458 · VCV2203557

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0933 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00738%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

age related macular degeneration 13

Computational evidence

Protein change
AlphaMissense	0.0933	likely benign
REVEL	0.156	moderately benign-leaning
SaProt	LLR -5.58	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP -1.1, phastCons 0.89
Regional constraint	o/e 1.00	unconstrained · MANE · 61 kb · p 0.95 · regional, not allelic
Overall
CADD	12.83	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00738% European (non-Finnish) · 87/1,179,622 alleles

Filtering AF 0.00605% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00565%

Overall 0.00552% 89/1,613,584 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00738%	13,559
Remaining individualsnot grpmax-eligible	0.0032%	31,234

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.Ile492Leu
Coding: c.1474A>C
MANE Select: NM_000204
dbSNP: rs200025458
Type: single nucleotide variant
Location: chr4:109742551 (GRCh38)
Gene constraint: LOEUF 1.076 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.50 · 2 PDB
Residue 492: a disulfide bond; the peptidase s1 domain

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

Disease context

Also linked: complement factor I deficiency atypical hemolytic-uremic syndrome with I factor anomaly

Similar variants

CFI p.Ile492Met Uncertain significance ★ ⚠ same residue
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

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-ile492leu (accessed [today's date]).

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