# NM_001710.6(CFB):c.221G>A (p.Arg74His)

https://sugi.bio/variant/cfb-p-arg74his

## Summary

**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.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs117314762 · 5 submitters · 2 linked conditions · AlphaMissense ambiguous · low-frequency (popmax 1.27%, eas)

## For patients & families {#patients}

This is a change in the CFB gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 5 submitters, 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.Arg74His |
| Coding change (HGVS c.) | c.221G>A |
| MANE Select transcript | [NM_001710](https://www.ncbi.nlm.nih.gov/nuccore/NM_001710) |
| dbSNP | [rs117314762](https://www.ncbi.nlm.nih.gov/snp/rs117314762/) |
| Variant type | single nucleotide variant |
| Location | chr6:31946529-31946529 (GRCh38) |
| ClinVar | [VCV356268](https://www.ncbi.nlm.nih.gov/clinvar/variation/356268/) |

**All HGVS expressions:** `LRG_136:g.5586G>A`, `LRG_136t1:c.221G>A`, `LRG_26:g.24041G>A`, `NC_000006.11:g.31914306G>A`, `NC_000006.12:g.31946529G>A`, `NG_008191.1:g.5586G>A`, `NG_011730.1:g.24041G>A`, `NM_001710.6:c.221G>A`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense and REVEL are indeterminate here — the available evidence is described below.

- AlphaMissense **ambiguous** (0.4734) — no call either way
- REVEL 0.431 (indeterminate)
- SaProt LLR -13.604 (damaging)
- Conservation: phyloP 11.782, GERP 1.73, phastCons 1 — highly conserved
- CADD: **PHRED 32.0**. 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 **1.27%** (eas) · FAF95 1.18% · FAF99 1.15% · 569/44,872 in the highest group · 601/1,613,030 alleles overall — low-frequency (popmax 1.27%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 1.27% | 79 |
| Remaining individuals (not 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 |

*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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-09-26.

**Submitter consensus:** conflicting (2 Likely benign, 2 Benign, 1 Uncertain significance).

**Submission history:** 5 submissions (2017–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Likely benign | criteria provided, single submitter | clinical testing | 2017-04-27 |
| Genome Diagnostics Laboratory, The Hospital for Sick Children | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-08-13 |
| Genomenon, Inc, Genomenon, Inc | Benign | criteria provided, single submitter | curation | 2025-09-26 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2023-12-18 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2025-09-04 |

## Associated conditions {#conditions}

[atypical hemolytic-uremic syndrome](https://sugi.bio/atlas/disease/atypical-hemolytic-uremic-syndrome/), [atypical hemolytic-uremic syndrome with B factor anomaly](https://sugi.bio/atlas/disease/atypical-hemolytic-uremic-syndrome-with-b-factor-anomaly/).

**Reported phenotype names (ClinVar):** Atypical hemolytic-uremic syndrome, Atypical hemolytic-uremic syndrome with B factor anomaly, not provided, not specified, HEMOLYTIC UREMIC SYNDROME, ATYPICAL, SUSCEPTIBILITY TO, 4, AHUS, SUSCEPTIBILITY TO, 4, AllHighlyPenetrant, none provided.

## Similar variants {#similar}

Related CFB variant pages (same residue, condition, or type): [CFB p.Arg74Cys](/variant/cfb-p-arg74cys), [CFB p.Arg74Ser](/variant/cfb-p-arg74ser), [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 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 356268). 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.*