Is CFB p.Arg546Trp (c.1636C>T) pathogenic?

CFB p.Arg546Trp (c.1636C>T) is classified Uncertain significance in CFB (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-04). AlphaMissense: likely benign (0.118); Very rare (popmax 0.00223%, eas).

How common is CFB p.Arg546Trp (c.1636C>T) in the general population?

CFB p.Arg546Trp (c.1636C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about CFB p.Arg546Trp (c.1636C>T)?

AlphaMissense predicts likely benign (score 0.118) — an in-silico prediction, not a clinical call.

CFB p.Arg546Trp

c.1636C>T · rs745920524 · VCV2879851

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.118 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.118	likely benign
REVEL	0.506	indeterminate
SaProt	LLR -10.14	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP -2.3, phastCons 0.75
Overall
CADD	21.6	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 0.00223% East Asian · 1/44,876 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000822% 12/1,460,708 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,876
South Asian	0.0022%	45,539
Admixed American	0.00167%	60,016
European (non-Finnish)	0.000678%	147,502

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.Arg546Trp
Coding: c.1636C>T
MANE Select: NM_001710
dbSNP: rs745920524
Type: single nucleotide variant
Location: chr6:31950630 (GRCh38)
Gene constraint: LOEUF 0.719 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.54 · 28 PDB
Residue 546: an α-helix; a disulfide bond; the peptidase s1 domain

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

Similar variants

CFB p.Arg546Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
CFB p.Arg546= Likely benign ★ same residue
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
CFB p.Arg117Trp 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-arg546trp (accessed [today's date]).

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