Is CFB p.Lys538Glu (c.1612A>G) pathogenic?

CFB p.Lys538Glu (c.1612A>G) is classified Uncertain significance in CFB (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-03-04). AlphaMissense: likely benign (0.1933); Very rare (popmax 6.85e-05%); Associated with CFB-related disorder.

What condition is associated with CFB p.Lys538Glu (c.1612A>G)?

CFB p.Lys538Glu (c.1612A>G) is associated with CFB-related disorder (ClinVar).

How common is CFB p.Lys538Glu (c.1612A>G) in the general population?

CFB p.Lys538Glu (c.1612A>G) is very rare (popmax 6.85e-05%) (gnomAD).

What do computational predictors say about CFB p.Lys538Glu (c.1612A>G)?

AlphaMissense predicts likely benign (score 0.1933) — an in-silico prediction, not a clinical call.

CFB p.Lys538Glu

c.1612A>G · rs1054553580 · VCV2634749

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1933 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.85e-05%)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

CFB-related disorder

Computational evidence

Protein change
AlphaMissense	0.1933	likely benign
REVEL	0.577	indeterminate
SaProt	LLR -10.46	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>T here scores Δ0.30 · evaluated, not missing
Constraint at this position
Conservation	phyloP 11	GERP 2, phastCons 1
Overall
CADD	23.9	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 6.85e-05%

Overall 6.85e-05% 1/1,460,508 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: CFB
Protein: p.Lys538Glu
Coding: c.1612A>G
MANE Select: NM_001710
dbSNP: rs1054553580
Type: single nucleotide variant
Location: chr6:31950391 (GRCh38)
Gene constraint: LOEUF 0.719 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.54 · 28 PDB
Residue 538: a β-strand; a disulfide bond; the peptidase s1 domain

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

Disease context

CFB-related disorder

Similar variants

CFB p.Thr316Ile Uncertain significance ★★ ⚠ same condition
CFB p.Gly396Arg Likely pathogenic ★ ⚠ same condition
CFB p.Ile647fs Likely pathogenic ★ same condition
CFB c.2140-1G>C Uncertain significance ★★ same type
CFB c.-3G>A Uncertain significance ★★ same type
CFB p.Ala162Val Uncertain significance ★★ ⚠ same type
CFB p.Ala289Val Uncertain significance ★★ same type
CFB p.Ala567Gly Uncertain significance ★★ ⚠ same type

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-lys538glu (accessed [today's date]).

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