# NM_001710.5(CFB):c.94C>T (p.Arg32Trp)

https://sugi.bio/variant/cfb-p-arg32trp

## Summary

**CFB p.Arg32Trp (c.94C>T)** is classified **Benign/Likely benign** in CFB (ClinVar, Multiple submitters, 11 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.084); Common (popmax 33.4%, afr) — too common for a highly-penetrant pathogenic allele; Associated with atypical hemolytic-uremic syndrome with B factor anomaly.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs12614 · 11 submitters · 5 linked conditions · AlphaMissense likely benign · common (popmax 33.4%, afr) — 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 11 submitters, and is linked to atypical hemolytic-uremic syndrome with B factor anomaly.

*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.*

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0018554/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.Arg32Trp |
| Coding change (HGVS c.) | c.94C>T |
| MANE Select transcript | [NM_001710](https://www.ncbi.nlm.nih.gov/nuccore/NM_001710) |
| dbSNP | [rs12614](https://www.ncbi.nlm.nih.gov/snp/rs12614/) |
| Variant type | single nucleotide variant |
| Location | chr6:31946402-31946402 (GRCh38) |
| ClinVar | [VCV16076](https://www.ncbi.nlm.nih.gov/clinvar/variation/16076/) |

**All HGVS expressions:** `LRG_136:g.5459C>T`, `LRG_136t1:c.94C>T`, `LRG_26:g.23914C>T`, `NC_000006.11:g.31914179C>T`, `NC_000006.12:g.31946402C>T`, `NG_008191.1:g.5459C>T`, `NG_011730.1:g.23914C>T`, `NM_001710.6:c.94C>T`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 33.4%, afr) — too common for a highly-penetrant pathogenic allele.

- AlphaMissense **likely benign** (0.084)
- REVEL 0.283 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -7.919 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP -2.396, GERP -3.46 — fast-evolving / accelerated position
- CADD: **PHRED 15.54**. 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 **33.4%** (afr) · FAF95 33.1% · FAF99 33% · 25,067/74,960 in the highest group · 175,694/1,612,892 alleles overall — common (popmax 33.4%, afr) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 33.4% | 3 |
| South Asian | 20.3% | 5 |
| Middle Eastern | 19.4% | 5 |
| Finnish (not grpmax-eligible) | 15.5% | 6 |
| Remaining individuals (not grpmax-eligible) | 11% | 9 |
| Admixed American | 10.8% | 9 |
| Ashkenazi Jewish (not grpmax-eligible) | 9.34% | 11 |
| Amish (not grpmax-eligible) | 8.99% | 11 |
| European (non-Finnish) | 8.64% | 12 |
| East Asian | 6.86% | 15 |

*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 **32** lies in a UniProt-annotated variant site (in allele s; may be associated with a reduced risk for age-related macular degeneration); a UniProt-annotated variant site (in).

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 2026-02-04.

**Submitter consensus:** conflicting (8 Benign, 3 Likely benign).

**Submission history:** 11 submissions (2013–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genome Diagnostics Laboratory, The Hospital for Sick Children | Benign | criteria provided, single submitter | clinical testing | 2022-09-27 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-21 |
| OMIM | Benign | no assertion criteria provided | literature only | 2013-10-28 |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2017-04-27 |
| Fulgent Genetics, Fulgent Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2022-05-09 |
| Genomenon, Inc, Genomenon, Inc | Benign | criteria provided, single submitter | curation | 2025-09-26 |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2021-06-09 |
| PreventionGenetics, part of Exact Sciences | Benign | no assertion criteria provided | clinical testing | 2019-07-02 |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | criteria provided, single submitter | clinical testing | 2022-09-28 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-04 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-26 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Atypical hemolytic-uremic syndrome with B factor anomaly, Factor B fast/slow polymorphism, Atypical hemolytic-uremic syndrome, not provided, Focal segmental glomerulosclerosis, Age related macular degeneration 14, Complement factor b deficiency, CFB-related disorder, not specified, HEMOLYTIC UREMIC SYNDROME, ATYPICAL, SUSCEPTIBILITY TO, 4.

## Similar variants {#similar}

Related CFB variant pages (same residue, condition, or type): [CFB p.Arg32Gly](/variant/cfb-p-arg32gly), [CFB p.Arg32Ter](/variant/cfb-p-arg32ter), [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).

### 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 16076). 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.*