# NM_001710.6(CFB):c.1598A>G (p.Lys533Arg)

https://sugi.bio/variant/cfb-p-lys533arg

## Summary

**CFB p.Lys533Arg (c.1598A>G)** is classified **Benign/Likely benign** in CFB (ClinVar, Multiple submitters, 14 submitters; last evaluated 2026-01-27). AlphaMissense: likely benign (0.0864); Common (popmax 6.01%, sas) — too common for a highly-penetrant pathogenic allele; Associated with age related macular degeneration 14.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs149101394 · 14 submitters · 5 linked conditions · AlphaMissense likely benign · common (popmax 6.01%, sas) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the CFB gene that is classified as benign/likely benign — not considered disease-causing, submitted by 14 submitters, and is linked to age related macular degeneration 14.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Diagnostic panels | CFB is a diagnostic-grade gene on 5 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0024978/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CFB](https://sugi.bio/atlas/gene/CFB/) |
| Protein change (HGVS p.) | p.Lys533Arg |
| Coding change (HGVS c.) | c.1598A>G |
| MANE Select transcript | [NM_001710](https://www.ncbi.nlm.nih.gov/nuccore/NM_001710) |
| dbSNP | [rs149101394](https://www.ncbi.nlm.nih.gov/snp/rs149101394/) |
| Variant type | single nucleotide variant |
| Location | chr6:31950377-31950377 (GRCh38) |
| ClinVar | [VCV225313](https://www.ncbi.nlm.nih.gov/clinvar/variation/225313/) |

**All HGVS expressions:** `LRG_136:g.9434A>G`, `LRG_136t1:c.1598A>G`, `NC_000006.11:g.31918154A>G`, `NC_000006.12:g.31950377A>G`, `NG_008191.1:g.9434A>G`, `NM_001710.6:c.1598A>G`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 6.01%, sas) — too common for a highly-penetrant pathogenic allele.

- AlphaMissense **likely benign** (0.0864)
- REVEL 0.491 (indeterminate)
- SaProt LLR -7.616 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- Conservation: phyloP 6.216, GERP 1.1, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 19.88**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **6.01%** (sas) · FAF95 5.88% · FAF99 5.82% · 5,474/91,086 in the highest group · 7,747/1,613,030 alleles overall — common (popmax 6.01%, sas) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 6.01% | 17 |
| African / African-American | 1.07% | 93 |
| Remaining individuals (not grpmax-eligible) | 0.699% | 143 |
| East Asian | 0.628% | 159 |
| Middle Eastern | 0.544% | 184 |
| Admixed American | 0.178% | 561 |
| European (non-Finnish) | 0.0507% | 1,973 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.0405% | 2,467 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**CFB** population constraint: LOEUF 0.719, pLI 1.4693e-10, missense-Z 2.7519. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **C3 glomerulonephritis** — Limited (AD)
- **atypical hemolytic-uremic syndrome with B factor anomaly** — Moderate (AD)

## Protein context {#protein}

Residue **533** lies in a β-strand; a disulfide bond; a UniProt-annotated variant site (in ahus4; benign); the peptidase s1 domain.

AlphaFold model confidence (whole protein): pLDDT 86.54, 65% of residues very-high.

**28 experimental structure(s)** (PDB): [11MG](https://www.rcsb.org/structure/11MG), [11MH](https://www.rcsb.org/structure/11MH), [1DLE](https://www.rcsb.org/structure/1DLE), [1Q0P](https://www.rcsb.org/structure/1Q0P), [1RRK](https://www.rcsb.org/structure/1RRK), [1RS0](https://www.rcsb.org/structure/1RS0).

## What this gene does {#gene-function}

*Describes the biological roles of CFB (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*


### Pathways affected {#pathways}

CFB participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Activation of C3 and C5](https://reactome.org/content/detail/R-HSA-174577) | curated |
| [Alternative complement activation](https://reactome.org/content/detail/R-HSA-173736) | curated |
| [Regulation of Complement cascade](https://reactome.org/content/detail/R-HSA-977606) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Biological process:** complement activation, alternative pathway.

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-27.

**Submitter consensus:** conflicting (9 Benign, 5 Likely benign).

**Submission history:** 14 submissions (2016–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center | Likely benign | criteria provided, single submitter | reference population | 2016-03-18 |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Benign | criteria provided, single submitter | clinical testing | 2016-03-28 |
| Genome Diagnostics Laboratory, The Hospital for Sick Children | Benign | criteria provided, single submitter | clinical testing | 2022-06-24 |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | criteria provided, single submitter | clinical testing | 2022-11-23 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-01-27 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-21 |
| Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Benign | criteria provided, single submitter | clinical testing | 2017-02-09 |
| Mendelics | Benign | criteria provided, single submitter | clinical testing | 2019-05-28 |
| Illumina Laboratory Services, Illumina | Likely benign | criteria provided, single submitter | clinical testing | 2017-04-27 |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2021-03-22 |
| Fulgent Genetics, Fulgent Genetics | Benign | criteria provided, single submitter | clinical testing | 2022-04-07 |
| Breakthrough Genomics, Breakthrough Genomics | Likely benign | criteria provided, single submitter | not provided |  |
| Genomenon, Inc, Genomenon, Inc | Benign | criteria provided, single submitter | curation | 2025-09-26 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-22 |

## Associated conditions {#conditions}

[age related macular degeneration 14](https://sugi.bio/atlas/disease/age-related-macular-degeneration-14/), [complement component 2 deficiency](https://sugi.bio/atlas/disease/complement-component-2-deficiency/), [atypical hemolytic-uremic syndrome with B factor anomaly](https://sugi.bio/atlas/disease/atypical-hemolytic-uremic-syndrome-with-b-factor-anomaly/), [complement factor b deficiency](https://sugi.bio/atlas/disease/complement-factor-b-deficiency/), [atypical hemolytic-uremic syndrome](https://sugi.bio/atlas/disease/atypical-hemolytic-uremic-syndrome/).

**Reported phenotype names (ClinVar):** Age related macular degeneration 14, Complement component 2 deficiency, Atypical hemolytic-uremic syndrome, not provided, not specified, Complement factor b deficiency, Atypical hemolytic-uremic syndrome with B factor anomaly, MACULAR DEGENERATION, AGE-RELATED, 14, REDUCED RISK OF, HEMOLYTIC UREMIC SYNDROME, ATYPICAL, SUSCEPTIBILITY TO, 4, AHUS, SUSCEPTIBILITY TO, 4.

## Similar variants {#similar}

Related CFB variant pages (same residue, condition, or type): [CFB c.-3G>A](/variant/cfb-c-minus-3g-a), [CFB p.Arg138Gln](/variant/cfb-p-arg138gln), [CFB p.Arg138Trp](/variant/cfb-p-arg138trp), [CFB p.Arg203Gln](/variant/cfb-p-arg203gln), [CFB p.Arg379Cys](/variant/cfb-p-arg379cys), [CFB p.Gln256Ter](/variant/cfb-p-gln256ter), [CFB p.Glu601Lys](/variant/cfb-p-glu601lys), [CFB p.Glu621Lys](/variant/cfb-p-glu621lys).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 225313). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*