Is CFI p.Ala452Asp (c.1355C>A) pathogenic?

CFI p.Ala452Asp (c.1355C>A) is classified Uncertain significance in CFI (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-04-26). AlphaMissense: likely pathogenic (0.9931); Absent from gnomAD v4.1; Associated with atypical hemolytic-uremic syndrome with I factor anomaly.

What condition is associated with CFI p.Ala452Asp (c.1355C>A)?

CFI p.Ala452Asp (c.1355C>A) is associated with atypical hemolytic-uremic syndrome with I factor anomaly (ClinVar).

How common is CFI p.Ala452Asp (c.1355C>A) in the general population?

CFI p.Ala452Asp (c.1355C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CFI p.Ala452Asp (c.1355C>A)?

AlphaMissense predicts likely pathogenic (score 0.9931) — an in-silico prediction, not a clinical call.

CFI p.Ala452Asp

c.1355C>A · rs1579164519 · VCV829951

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9931 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

atypical hemolytic-uremic syndrome with I factor anomaly

Computational evidence

Protein change
AlphaMissense	0.9931	likely pathogenic · top 2% in CFI
REVEL	0.856	moderately pathogenic-leaning
SaProt	LLR -12.09	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.7, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 61 kb · p 0.95 · regional, not allelic
Overall
CADD	24.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CFI
Protein: p.Ala452Asp
Coding: c.1355C>A
MANE Select: NM_000204
dbSNP: rs1579164519
Type: single nucleotide variant
Location: chr4:109746296 (GRCh38)
Gene constraint: LOEUF 1.076 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.50 · 2 PDB
Residue 452: an α-helix; a disulfide bond; 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.Ala452Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
CFI p.Ala452Pro Likely pathogenic ★ ⚠ same residue
CFI p.Ala452Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
CFI p.Ala452= Likely benign ★ 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

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-ala452asp (accessed [today's date]).

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