Is CFB p.Met458Ile (c.1374G>A) pathogenic?

CFB p.Met458Ile (c.1374G>A) is classified Conflicting classifications of pathogenicity in CFB (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2024-11-27). AlphaMissense: ambiguous (0.3775); Very rare (popmax 0.00424%, nfe); Associated with atypical hemolytic-uremic syndrome with B factor anomaly.

What condition is associated with CFB p.Met458Ile (c.1374G>A)?

CFB p.Met458Ile (c.1374G>A) is associated with atypical hemolytic-uremic syndrome with B factor anomaly, age related macular degeneration 14, complement factor b deficiency (ClinVar).

How common is CFB p.Met458Ile (c.1374G>A) in the general population?

CFB p.Met458Ile (c.1374G>A) is very rare (popmax 0.00424%, nfe) (gnomAD).

What do computational predictors say about CFB p.Met458Ile (c.1374G>A)?

AlphaMissense predicts ambiguous (score 0.3775) — an in-silico prediction, not a clinical call.

CFB p.Met458Ile

c.1374G>A · rs200837114 · VCV829990

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

ambiguous

0.3775 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00424%, nfe)

Conditions

atypical hemolytic-uremic syndrome with B factor anomaly

Computational evidence

Protein change
AlphaMissense	0.3775	ambiguous
REVEL	0.373	indeterminate
SaProt	LLR -7.06	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.3	GERP 2, phastCons 1
Overall
CADD	16.83	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 0.00424% European (non-Finnish) · 50/1,180,044 alleles

Filtering AF 0.00326% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00294%

Overall 0.00316% 51/1,613,242 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00424%	23,601
African / African-American	0.00133%	74,936

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.Met458Ile
Coding: c.1374G>A
MANE Select: NM_001710
dbSNP: rs200837114
Type: single nucleotide variant
Location: chr6:31949523 (GRCh38)
Gene constraint: LOEUF 0.719 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.54 · 28 PDB
Residue 458: an α-helix; a UniProt-annotated variant site (in ahus4); the vwfa domain

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

Disease context

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

Also linked: age related macular degeneration 14 complement factor b deficiency atypical hemolytic-uremic syndrome

Similar variants

CFB p.Met458Thr 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
CFB p.Glu601Lys 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-met458ile (accessed [today's date]).

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