# NM_000186.4(CFH):c.2880del (p.Phe960fs)

https://sugi.bio/variant/cfh-p-phe960fs

## Summary

**CFH p.Phe960fs (c.2880del)** is classified **Pathogenic/Likely pathogenic** in CFH (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-02). Very rare (popmax 8.47e-05%, nfe); Associated with atypical hemolytic-uremic syndrome.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · 2 submitters · 1 linked condition · very rare (popmax 8.47e-05%, nfe)

## For patients & families {#patients}

This is a change in the CFH gene that is considered likely disease-causing, submitted by 2 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 | CFH is a diagnostic-grade gene on 7 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 | [CFH](https://sugi.bio/atlas/gene/CFH/) |
| Protein change (HGVS p.) | p.Phe960fs |
| Coding change (HGVS c.) | c.2880del |
| MANE Select transcript | [NM_000186](https://www.ncbi.nlm.nih.gov/nuccore/NM_000186) |
| Variant type | Deletion |
| Location | chr1:196740713-196740713 (GRCh38) |
| ClinVar | [VCV4291518](https://www.ncbi.nlm.nih.gov/clinvar/variation/4291518/) |

**All HGVS expressions:** `LRG_47:g.93706del`, `LRG_47t1:c.2880del`, `NC_000001.10:g.196709846del`, `NC_000001.11:g.196740716del`, `NG_007259.1:g.93706del`, `NM_000186.4:c.2880del`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 7.125, GERP 1.06, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. the gene is **loss-of-function-intolerant** (LOEUF 0.43, pLI 0.99998), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 18 of 22**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **8.47e-05%** (nfe) · 1/1,179,942 in the highest group · 1/1,613,932 alleles overall — very rare (popmax 8.47e-05%, nfe).

*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}

**CFH** population constraint: LOEUF 0.43, pLI 0.99998, missense-Z 1.4706. *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** — Definitive (AR)
- **atypical hemolytic-uremic syndrome** — Definitive (SD)

## Protein context {#protein}

Residue **960** lies in the sushi 16 domain.

AlphaFold model confidence (whole protein): pLDDT 78.54, 1% of residues very-high.

**51 experimental structure(s)** (PDB): [1HAQ](https://www.rcsb.org/structure/1HAQ), [1HCC](https://www.rcsb.org/structure/1HCC), [1HFH](https://www.rcsb.org/structure/1HFH), [1HFI](https://www.rcsb.org/structure/1HFI), [2BZM](https://www.rcsb.org/structure/2BZM), [2G7I](https://www.rcsb.org/structure/2G7I) — incl. mutant structure 2UWN.

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

*Describes the biological roles of CFH (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.*

**How this variant is thought to act:** CFH's established molecular role includes heparin binding. p.Phe960fs falls in the sushi 16 domain.


### Pathways affected {#pathways}

CFH participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Regulation of Complement cascade](https://reactome.org/content/detail/R-HSA-977606) | curated |

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

**Molecular function:** heparin binding, identical protein binding, heparan sulfate proteoglycan binding.

**Biological process:** proteolysis, inflammatory response, complement activation, complement activation, alternative pathway, central nervous system myelination, regulation of complement activation.

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-10-02.

**Submitter consensus:** conflicting (1 Pathogenic, 1 Likely pathogenic).

**Submission history:** 2 submissions (2020–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genomenon, Inc, Genomenon, Inc | Pathogenic | criteria provided, single submitter | curation | 2025-10-02 |
| Blueprint Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2020-02-06 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Atypical hemolytic-uremic syndrome, CFH-related disorder, CFH-related condition, CFH-related disorders.

## Similar variants {#similar}

Related CFH variant pages (same residue, condition, or type): [CFH p.Phe960Ser](/variant/cfh-p-phe960ser), [CFH p.Ala415fs](/variant/cfh-p-ala415fs), [CFH p.Leu750_Lys751del](/variant/cfh-p-leu750-lys751del), [CFH c.350+1del](/variant/cfh-c-350-plus-1del), [CFH p.Arg885fs](/variant/cfh-p-arg885fs), [CFH p.Asp748fs](/variant/cfh-p-asp748fs), [CFH p.Cys16fs](/variant/cfh-p-cys16fs), [CFH p.Lys1162fs](/variant/cfh-p-lys1162fs).

### 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 4291518). 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.*