Is CFI p.Ile140Thr (c.419T>C) pathogenic?

CFI p.Ile140Thr (c.419T>C) is classified Uncertain significance in CFI (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-26). AlphaMissense: likely pathogenic (0.6498); Very rare (popmax 0.00167%, amr); Associated with atypical hemolytic-uremic syndrome with I factor anomaly.

What condition is associated with CFI p.Ile140Thr (c.419T>C)?

CFI p.Ile140Thr (c.419T>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.Ile140Thr (c.419T>C) in the general population?

CFI p.Ile140Thr (c.419T>C) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about CFI p.Ile140Thr (c.419T>C)?

AlphaMissense predicts likely pathogenic (score 0.6498) — an in-silico prediction, not a clinical call.

CFI p.Ile140Thr

c.419T>C · rs765780615 · VCV2885271

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.6498 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

atypical hemolytic-uremic syndrome with I factor anomaly

Computational evidence

Protein change
AlphaMissense	0.6498	likely pathogenic
REVEL	0.256	benign-leaning
SaProt	LLR -9.86	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7	GERP 1.8, phastCons 0.96
Regional constraint	o/e 1.00	unconstrained · MANE · 61 kb · p 0.95 · regional, not allelic
Overall
CADD	21.8	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 0.00167% Admixed American · 1/60,024 alleles

Overall 0.000137% 2/1,461,858 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,024
European (non-Finnish)	8.47e-05%	1,180,020

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.Ile140Thr
Coding: c.419T>C
MANE Select: NM_000204
dbSNP: rs765780615
Type: single nucleotide variant
Location: chr4:109764600 (GRCh38)
Gene constraint: LOEUF 1.076 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.50 · 2 PDB
Residue 140: a disulfide bond; the srcr domain; a β-strand

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 atypical hemolytic-uremic syndrome

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-ile140thr (accessed [today's date]).

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