Is CFI p.Asp519Asn (c.1555G>A) pathogenic?

CFI p.Asp519Asn (c.1555G>A) is classified Conflicting classifications of pathogenicity in CFI (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-09-26). AlphaMissense: likely pathogenic (0.9695); Very rare (popmax 0.0022%, sas); Associated with CFI-related disorder.

What condition is associated with CFI p.Asp519Asn (c.1555G>A)?

CFI p.Asp519Asn (c.1555G>A) is associated with CFI-related disorder, atypical hemolytic-uremic syndrome with I factor anomaly (ClinVar).

How common is CFI p.Asp519Asn (c.1555G>A) in the general population?

CFI p.Asp519Asn (c.1555G>A) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about CFI p.Asp519Asn (c.1555G>A)?

AlphaMissense predicts likely pathogenic (score 0.9695) — an in-silico prediction, not a clinical call.

CFI p.Asp519Asn

c.1555G>A · rs121964918 · VCV12126

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9695 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CFI-related disorder

Computational evidence

Protein change
AlphaMissense	0.9695	likely pathogenic · top 8% in CFI
REVEL	0.846	moderately pathogenic-leaning
SaProt	LLR -9.88	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.23	loss · gain 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 7.6	GERP 1.4, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 61 kb · p 0.95 · regional, not allelic
Overall
CADD	29.5	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 0.0022% South Asian · 2/91,080 alleles

Filtering AF 0.000542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.000929% 15/1,614,004 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,540
Remaining individualsnot grpmax-eligible	0.0016%	62,488
European (non-Finnish)	0.00102%	98,333

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.Asp519Asn
Coding: c.1555G>A
MANE Select: NM_000204
dbSNP: rs121964918
Type: single nucleotide variant
Location: chr4:109741090 (GRCh38)
Gene constraint: LOEUF 1.076 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.50 · 2 PDB
Residue 519: a disulfide bond; a UniProt-annotated variant site (in ahus3); the peptidase s1 domain

Full CFI gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Also linked: atypical hemolytic-uremic syndrome with I factor anomaly

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 p.Trp145Ter 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-asp519asn (accessed [today's date]).

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