# NM_001710.6(CFB):c.991A>G (p.Asn331Asp)

https://sugi.bio/variant/cfb-p-asn331asp

## Summary

**CFB p.Asn331Asp (c.991A>G)** is classified **Likely pathogenic** in CFB (ClinVar, Single submitter, 1 submitter; last evaluated 2026-09-17). AlphaMissense: likely benign (0.0554); Ultra-rare (popmax 0.0601%, eas); Associated with atypical hemolytic-uremic syndrome.

**At a glance:** Likely pathogenic · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense likely benign · ultra-rare (popmax 0.0601%, eas)

## For patients & families {#patients}

This is a change in the CFB gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to atypical hemolytic-uremic syndrome.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant, Autosomal recessive, Not applicable |
| Age of onset (of this condition) | All ages |
| Prevalence | 1-9 / 1 000 000 (United States) |
| Clinical trials | 40 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | CFB is a diagnostic-grade gene on 5 Genomics England panels |

**Commonly reported features of Atypical hemolytic uremic syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Proteinuria — Very frequent (99-80%)
- Hematuria — Very frequent (99-80%)
- Abnormality of blood and blood-forming tissues — Very frequent (99-80%)
- Thrombocytopenia — Very frequent (99-80%)
- Acute kidney injury — Very frequent (99-80%)
- Microangiopathic hemolytic anemia — Very frequent (99-80%)
- Abnormality of metabolism/homeostasis — Very frequent (99-80%)
- Abnormal lactate dehydrogenase activity — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0008702/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.Asn331Asp |
| Coding change (HGVS c.) | c.991A>G |
| MANE Select transcript | [NM_001710](https://www.ncbi.nlm.nih.gov/nuccore/NM_001710) |
| Variant type | single nucleotide variant |
| Location | chr6:31948467-31948467 (GRCh38) |
| ClinVar | [VCV4280400](https://www.ncbi.nlm.nih.gov/clinvar/variation/4280400/) |

**All HGVS expressions:** `LRG_136:g.7524A>G`, `LRG_136t1:c.991A>G`, `NC_000006.11:g.31916244A>G`, `NC_000006.12:g.31948467A>G`, `NG_008191.1:g.7524A>G`, `NM_001710.6:c.991A>G`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — AlphaMissense predicts likely-benign.

- AlphaMissense **likely benign** (0.0554) — ⚠ discordant with the pathogenic call
- REVEL 0.227 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.581 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 2.077, GERP -3.85, phastCons 0.983 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 4.967**. 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 **0.0601%** (eas) · FAF95 0.0424% · FAF99 0.0364% · 27/44,904 in the highest group · 27/1,614,114 alleles overall — ultra-rare (popmax 0.0601%, eas).

*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 **331** lies in the vwfa 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}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2026-09-17.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genomenon, Inc, Genomenon, Inc | Likely pathogenic | criteria provided, single submitter | curation | 2026-09-17 |

## Associated conditions {#conditions}

[atypical hemolytic-uremic syndrome](https://sugi.bio/atlas/disease/atypical-hemolytic-uremic-syndrome/).

**Reported phenotype names (ClinVar):** Atypical hemolytic-uremic syndrome.

## Similar variants {#similar}

Related CFB variant pages (same residue, condition, or type): [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.Ser284Asn](/variant/cfb-p-ser284asn), [CFB c.1036+111A>G](/variant/cfb-c-1036-plus-111a-g).

### 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 4280400). 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.*