Is CFI p.Ile235= (c.705T>C) pathogenic?

CFI p.Ile235= (c.705T>C) is classified Likely benign in CFI (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-06-13). Ultra-rare (popmax 0.0347%, afr); Associated with atypical hemolytic-uremic syndrome with I factor anomaly.

What condition is associated with CFI p.Ile235= (c.705T>C)?

CFI p.Ile235= (c.705T>C) is associated with atypical hemolytic-uremic syndrome with I factor anomaly, complement factor I deficiency, age related macular degeneration 13 (ClinVar).

How common is CFI p.Ile235= (c.705T>C) in the general population?

CFI p.Ile235= (c.705T>C) is ultra-rare (popmax 0.0347%, afr) (gnomAD).

CFI p.Ile235=

c.705T>C · rs373891906 · VCV1592730

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0347%, afr)

Conditions

atypical hemolytic-uremic syndrome with I factor anomaly

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 1.2	GERP 0.48, phastCons 0.072
Overall
CADD	4.463	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0347% African / African-American · 26/74,994 alleles

Filtering AF 0.0242% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0208%

Overall 0.00161% 26/1,611,192 alleles · ultra-rare exomes 11/1,458,870 · genomes 15/152,322 · joint denominator

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.Ile235=
Coding: c.705T>C
MANE Select: NM_000204
dbSNP: rs373891906
Type: single nucleotide variant
Location: chr4:109760590 (GRCh38)
Gene constraint: LOEUF 1.076 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.50 · 2 PDB
Residue 235: the ldl-receptor class a 1 domain

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

Disease context

atypical hemolytic-uremic syndrome with I factor anomaly — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: complement factor I deficiency age related macular degeneration 13

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-ile235 (accessed [today's date]).

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