Is CFB p.Ile469Met (c.1407C>G) pathogenic?

CFB p.Ile469Met (c.1407C>G) is classified Conflicting classifications of pathogenicity in CFB (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-09-17). AlphaMissense: likely benign (0.1532); Ultra-rare (popmax 0.0197%, nfe); Associated with atypical hemolytic-uremic syndrome.

What condition is associated with CFB p.Ile469Met (c.1407C>G)?

CFB p.Ile469Met (c.1407C>G) is associated with atypical hemolytic-uremic syndrome, macular degeneration, atypical hemolytic-uremic syndrome with B factor anomaly (ClinVar).

How common is CFB p.Ile469Met (c.1407C>G) in the general population?

CFB p.Ile469Met (c.1407C>G) is ultra-rare (popmax 0.0197%, nfe) (gnomAD).

How is Atypical hemolytic uremic syndrome inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CFB p.Ile469Met (c.1407C>G)?

AlphaMissense predicts likely benign (score 0.1532) — an in-silico prediction, not a clinical call.

CFB p.Ile469Met

c.1407C>G · rs201798809 · VCV356288

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1532 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0197%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

atypical hemolytic-uremic syndrome

Computational evidence

Protein change
AlphaMissense	0.1532	likely benign
REVEL	0.432	indeterminate
SaProt	LLR -7.12	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.19	GERP -3.4, phastCons 0.65
Overall
CADD	19.76	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 0.0197% European (non-Finnish) · 232/1,180,028 alleles

Filtering AF 0.0176% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0168%

Overall 0.0149% 240/1,612,996 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0197%	5,086
Admixed American	0.005%	20,008
Finnishnot grpmax-eligible	0.00318%	31,445
African / African-American	0.00267%	37,518
Remaining individualsnot grpmax-eligible	0.0016%	62,496

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: CFB
Protein: p.Ile469Met
Coding: c.1407C>G
MANE Select: NM_001710
dbSNP: rs201798809
Type: single nucleotide variant
Location: chr6:31949556 (GRCh38)
Gene constraint: LOEUF 0.719 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.54 · 28 PDB
Residue 469: the vwfa domain

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

Disease context

atypical hemolytic-uremic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: macular degeneration atypical hemolytic-uremic syndrome with B factor anomaly

For Atypical hemolytic uremic syndrome (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Not applicable
Onset: All ages
Prevalence: 1-9 / 1 000 000 (United States)

Similar variants

CFB p.Ile469= Uncertain significance ★ same residue
CFB p.Ile469Phe Uncertain significance ★ same residue
CFB c.-3G>A Uncertain significance ★★ same condition
CFB p.Arg138Gln Uncertain significance ★★ ⚠ same condition
CFB p.Arg138Trp Uncertain significance ★★ ⚠ same condition
CFB p.Arg203Gln Uncertain significance ★★ same condition
CFB p.Arg379Cys Uncertain significance ★★ same condition
CFB p.Gln256Ter 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/cfb-p-ile469met (accessed [today's date]).

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