Is CFB p.Arg74His (c.221G>A) pathogenic?

CFB p.Arg74His (c.221G>A) is classified Conflicting classifications of pathogenicity in CFB (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-09-26). AlphaMissense: ambiguous (0.4734); Low-frequency (popmax 1.27%, eas); Associated with atypical hemolytic-uremic syndrome.

What condition is associated with CFB p.Arg74His (c.221G>A)?

CFB p.Arg74His (c.221G>A) is associated with atypical hemolytic-uremic syndrome, atypical hemolytic-uremic syndrome with B factor anomaly (ClinVar).

How common is CFB p.Arg74His (c.221G>A) in the general population?

CFB p.Arg74His (c.221G>A) is low-frequency (popmax 1.27%, eas) (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.Arg74His (c.221G>A)?

AlphaMissense predicts ambiguous (score 0.4734) — an in-silico prediction, not a clinical call.

CFB p.Arg74His

c.221G>A · rs117314762 · VCV356268

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

ambiguous

0.4734 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.27%, eas)

Conditions

atypical hemolytic-uremic syndrome

Computational evidence

Protein change
AlphaMissense	0.4734	ambiguous
REVEL	0.431	indeterminate
SaProt	LLR -13.60	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Overall
CADD	32.0	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 1.27% East Asian · 569/44,872 alleles

Filtering AF 1.18% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.15%

Overall 0.0373% 601/1,613,030 alleles · low-frequency

Ancestry group	Frequency	1 in
East Asiangrpmax	1.27%	79
Remaining individualsnot grpmax-eligible	0.0304%	3,289
South Asian	0.00439%	22,772
Admixed American	0.00333%	30,012
European (non-Finnish)	0.000593%	168,578

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.Arg74His
Coding: c.221G>A
MANE Select: NM_001710
dbSNP: rs117314762
Type: single nucleotide variant
Location: chr6:31946529 (GRCh38)
Gene constraint: LOEUF 0.719 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.54 · 28 PDB
Residue 74: a disulfide bond; the sushi 1 domain; a β-strand

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: 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.Arg74Cys Uncertain significance ★★ ⚠ same residue
CFB p.Arg74Ser 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-arg74his (accessed [today's date]).

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