Is CFI c.57+4A>G pathogenic?

CFI c.57+4A>G is classified Conflicting classifications of pathogenicity in CFI (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-08-15). Very rare (popmax 0.000685%, nfe); Associated with atypical hemolytic-uremic syndrome with I factor anomaly.

What condition is associated with CFI c.57+4A>G?

CFI c.57+4A>G is associated with atypical hemolytic-uremic syndrome with I factor anomaly (ClinVar).

How common is CFI c.57+4A>G in the general population?

CFI c.57+4A>G is very rare (popmax 0.000685%, nfe) (gnomAD).

CFI c.57+4A>G

rs757464411 · VCV899594

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000685%, nfe)

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
Splice region	donor +4	donor splice region (+4, within the first 6 intronic nt) · inside the BP7-excluded zone
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.26	loss · gain 0.01 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 3.1	GERP 0.9, phastCons 1
Non-coding constraint	Z 0.24	1 kb window · o/e 0.98 · regional · uncalibrated
Overall
CADD	16.91	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000685% European (non-Finnish) · 8/1,168,202 alleles

Filtering AF 0.000295% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000213%

Overall 0.00394% 63/1,600,058 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.173%	578
Remaining individualsnot grpmax-eligible	0.00646%	15,491
European (non-Finnish)grpmax	0.000685%	146,025

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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
Coding: c.57+4A>G
MANE Select: NM_000204
dbSNP: rs757464411
Type: single nucleotide variant
Location: chr4:109801911 (GRCh38)
Gene constraint: LOEUF 1.076 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.50 · 2 PDB

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 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
CFI c.940+6C>A 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-c-57-plus-4a-g (accessed [today's date]).

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