# NM_000204.5(CFI):c.1440_1441del (p.Arg480fs)

https://sugi.bio/variant/cfi-p-arg480fs

## Summary

**CFI p.Arg480fs (c.1440_1441del)** is classified **Pathogenic** in CFI (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-21). Very rare (popmax 0.0022%, sas).

**At a glance:** Pathogenic · review: Single submitter · rsID rs1283565272 · 1 submitter · very rare (popmax 0.0022%, sas)

## For patients & families {#patients}

This is a change in the CFI gene that is reported as disease-causing, but on limited review, submitted by 1 submitter.

*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 | [CFI](https://sugi.bio/atlas/gene/CFI/) |
| Protein change (HGVS p.) | p.Arg480fs |
| Coding change (HGVS c.) | c.1440_1441del |
| MANE Select transcript | [NM_000204](https://www.ncbi.nlm.nih.gov/nuccore/NM_000204) |
| dbSNP | [rs1283565272](https://www.ncbi.nlm.nih.gov/snp/rs1283565272/) |
| Variant type | Microsatellite |
| Location | chr4:109742584-109742585 (GRCh38) |
| ClinVar | [VCV2022339](https://www.ncbi.nlm.nih.gov/clinvar/variation/2022339/) |

**All HGVS expressions:** `LRG_48:g.64399AG[1]`, `LRG_48t1:c.1438_1439AG[1]`, `NC_000004.11:g.110663740CT[1]`, `NC_000004.12:g.109742584CT[1]`, `NG_007569.1:g.64399AG[1]`, `NM_000204.5:c.1440_1441del`, `NM_001318057.2:c.1464_1465del`, `NM_001331035.2:c.1419_1420del`, `NM_001375278.1:c.1464_1465del`, `NM_001375279.1:c.1440_1441del`, `NM_001375280.1:c.1419_1420del`, `NM_001375281.1:c.1440_1441del`, `NM_001375282.1:c.1419_1420del`, `NM_001375283.1:c.1383_1384del`, `NM_001375284.1:c.831_832del`, `NR_164671.1:n.1185AG[1]`, `NR_164672.1:n.1488AG[1]`, `NR_164673.1:n.1462AG[1]`

## 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 4.557, GERP 1.29, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.076, pLI 4.9115e-15. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 12 of 13**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no microsatellite 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 **0.0022%** (sas) · FAF95 0.000365% · FAF99 0.000137% · 2/90,958 in the highest group · 3/1,455,254 alleles overall — very rare (popmax 0.0022%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.0022% | 45,479 |
| Admixed American | 0.00167% | 59,976 |

*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}

**CFI** population constraint: LOEUF 1.076, pLI 4.9115e-15, missense-Z 0.28073. *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):

- **atypical hemolytic-uremic syndrome** — Definitive (AD)
- **C3 glomerulonephritis** — Moderate (AD)

## Protein context {#protein}

Residue **480** lies in a disulfide bond; the peptidase s1 domain.

AlphaFold model confidence (whole protein): pLDDT 84.50, 58% of residues very-high.

**2 experimental structure(s)** (PDB): [2XRC](https://www.rcsb.org/structure/2XRC), [5O32](https://www.rcsb.org/structure/5O32).

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

*Describes the biological roles of CFI (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}

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

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

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-07-21.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-07-21 |

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

## Similar variants {#similar}

Related CFI variant pages (same residue, condition, or type): [CFI p.Trp393fs](/variant/cfi-p-trp393fs), [CFI c.57+5_57+8del](/variant/cfi-c-57-plus-5-57-plus-8del), [CFI p.Cys550fs](/variant/cfi-p-cys550fs), [CFI p.Arg202del](/variant/cfi-p-arg202del), [CFI c.57+1GTAA[3]](/variant/cfi-c-57-plus-1gtaa-3), [CFI c.883+322TTGT[4]](/variant/cfi-c-883-plus-322ttgt-4).

### 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 2022339). 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.*