Is CFI p.Cys373Ser (c.1118G>C) pathogenic?

CFI p.Cys373Ser (c.1118G>C) is classified Likely pathogenic in CFI (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-07-02). AlphaMissense: likely pathogenic (0.9778); Very rare (popmax 8.47e-05%, nfe); Associated with atypical hemolytic-uremic syndrome with I factor anomaly.

What condition is associated with CFI p.Cys373Ser (c.1118G>C)?

CFI p.Cys373Ser (c.1118G>C) is associated with atypical hemolytic-uremic syndrome with I factor anomaly (ClinVar).

How common is CFI p.Cys373Ser (c.1118G>C) in the general population?

CFI p.Cys373Ser (c.1118G>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about CFI p.Cys373Ser (c.1118G>C)?

AlphaMissense predicts likely pathogenic (score 0.9778) — an in-silico prediction, not a clinical call.

CFI p.Cys373Ser

c.1118G>C · rs1579173999 · VCV829988

Likely pathogenic No assertion criteria

Classification

Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9778 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

atypical hemolytic-uremic syndrome with I factor anomaly

Computational evidence

Protein change
AlphaMissense	0.9778	likely pathogenic ✓ concordant with ClinVar · top 6% in CFI
REVEL	0.767	pathogenic-leaning
SaProt	LLR -10.38	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 1.6, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 61 kb · p 0.95 · regional, not allelic
Overall
CADD	26.9	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 8.47e-05% European (non-Finnish) · 1/1,179,996 alleles

Overall 6.84e-05% 1/1,461,840 alleles · very rare

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.Cys373Ser
Coding: c.1118G>C
MANE Select: NM_000204
dbSNP: rs1579173999
Type: single nucleotide variant
Location: chr4:109749248 (GRCh38)
Gene constraint: LOEUF 1.076 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.50 · 2 PDB
Residue 373: 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.Cys373Tyr 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-cys373ser (accessed [today's date]).

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