Is CFI p.Phe461Leu (c.1381T>C) pathogenic?

CFI p.Phe461Leu (c.1381T>C) is classified Uncertain significance in CFI (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-11-11). AlphaMissense: likely pathogenic (0.9758); Ultra-rare (popmax 0.0165%, mid); Associated with atypical hemolytic-uremic syndrome with I factor anomaly.

What condition is associated with CFI p.Phe461Leu (c.1381T>C)?

CFI p.Phe461Leu (c.1381T>C) is associated with atypical hemolytic-uremic syndrome with I factor anomaly (ClinVar).

How common is CFI p.Phe461Leu (c.1381T>C) in the general population?

CFI p.Phe461Leu (c.1381T>C) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about CFI p.Phe461Leu (c.1381T>C)?

AlphaMissense predicts likely pathogenic (score 0.9758) — an in-silico prediction, not a clinical call.

CFI p.Phe461Leu

c.1381T>C · rs886058983 · VCV347155

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9758 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

atypical hemolytic-uremic syndrome with I factor anomaly

Computational evidence

Protein change
AlphaMissense	0.9758	likely pathogenic · top 7% in CFI
REVEL	0.661	pathogenic-leaning
SaProt	LLR -8.45	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.7, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 61 kb · p 0.95 · regional, not allelic
Overall
CADD	24.3	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 0.0165% Middle Eastern · 1/6,062 alleles

Overall 0.000137% 2/1,461,856 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
European (non-Finnish)	8.47e-05%	1,180,018

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.Phe461Leu
Coding: c.1381T>C
MANE Select: NM_000204
dbSNP: rs886058983
Type: single nucleotide variant
Location: chr4:109746270 (GRCh38)
Gene constraint: LOEUF 1.076 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.50 · 2 PDB
Residue 461: the peptidase s1 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

Similar variants

CFI p.Phe461Ser 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.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-phe461leu (accessed [today's date]).

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