# NM_001710.6(CFB):c.220C>T (p.Arg74Cys)

https://sugi.bio/variant/cfb-p-arg74cys

## Summary

**CFB p.Arg74Cys (c.220C>T)** is classified **Uncertain significance** in CFB (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-13). AlphaMissense: likely pathogenic (0.7139); Very rare (popmax 0.004%, afr); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs760926358 · 2 submitters · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 0.004%, afr)

## For patients & families {#patients}

This is a change in the CFB gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, and is linked to Inborn genetic diseases.

*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:** [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.Arg74Cys |
| Coding change (HGVS c.) | c.220C>T |
| MANE Select transcript | [NM_001710](https://www.ncbi.nlm.nih.gov/nuccore/NM_001710) |
| dbSNP | [rs760926358](https://www.ncbi.nlm.nih.gov/snp/rs760926358/) |
| Variant type | single nucleotide variant |
| Location | chr6:31946528-31946528 (GRCh38) |
| ClinVar | [VCV1382472](https://www.ncbi.nlm.nih.gov/clinvar/variation/1382472/) |

**All HGVS expressions:** `LRG_136:g.5585C>T`, `LRG_136t1:c.220C>T`, `LRG_26:g.24040C>T`, `NC_000006.11:g.31914305C>T`, `NC_000006.12:g.31946528C>T`, `NG_008191.1:g.5585C>T`, `NG_011730.1:g.24040C>T`, `NM_001710.5:c.220C>T`, `NM_001710.6:c.220C>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.7139)
- REVEL 0.456 (indeterminate)
- SaProt LLR -14.719 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL makes no call
- Conservation: phyloP 4.838, GERP 1.73, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 28.4**. 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: **below the reporting threshold**. This position is scored for a different substitution (C>G, Δ0.37 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.004%** (afr) · FAF95 0.00106% · FAF99 0.000495% · 3/74,914 in the highest group · 12/1,612,912 alleles overall — very rare (popmax 0.004%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.004% | 24,971 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,476 |
| Finnish (not grpmax-eligible) | 0.00159% | 62,884 |
| European (non-Finnish) | 0.000593% | 168,579 |

*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 **74** lies in the sushi 1 domain; a β-strand.

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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-01-13.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2021–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-10-20 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-01-13 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases, not provided, none provided.

## Similar variants {#similar}

Related CFB variant pages (same residue, condition, or type): [CFB p.Arg74Ser](/variant/cfb-p-arg74ser), [CFB p.Arg74His](/variant/cfb-p-arg74his), [CFB p.Ala162Val](/variant/cfb-p-ala162val), [CFB p.Ala289Val](/variant/cfb-p-ala289val), [CFB p.Ala567Gly](/variant/cfb-p-ala567gly), [CFB p.Arg117Trp](/variant/cfb-p-arg117trp), [CFB p.Arg193Gln](/variant/cfb-p-arg193gln), [CFB p.Arg419Lys](/variant/cfb-p-arg419lys).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 1382472). 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.*