# NM_000204.5(CFI):c.1420C>T (p.Arg474Ter)

https://sugi.bio/variant/cfi-p-arg474ter

## Summary

**CFI p.Arg474Ter (c.1420C>T)** is classified **Pathogenic/Likely pathogenic** in CFI (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-09-26). Very rare (popmax 0.00439%, sas); Associated with CFI-related disorder.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs121964913 · 7 submitters · 4 linked conditions · very rare (popmax 0.00439%, sas)

## For patients & families {#patients}

This is a change in the CFI gene that is considered likely disease-causing, submitted by 7 submitters, and is linked to CFI-related disorder.

*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.Arg474Ter |
| Coding change (HGVS c.) | c.1420C>T |
| MANE Select transcript | [NM_000204](https://www.ncbi.nlm.nih.gov/nuccore/NM_000204) |
| dbSNP | [rs121964913](https://www.ncbi.nlm.nih.gov/snp/rs121964913/) |
| Variant type | single nucleotide variant |
| Location | chr4:109746231-109746231 (GRCh38) |
| ClinVar | [VCV12121](https://www.ncbi.nlm.nih.gov/clinvar/variation/12121/) |

**All HGVS expressions:** `LRG_48:g.60755C>T`, `NC_000004.11:g.110667387G>A`, `NC_000004.12:g.109746231G>A`, `NG_007569.1:g.60755C>T`, `NM_000204.4:c.1420C>T`, `NM_000204.5:c.1420C>T`, `NM_001318057.2:c.1444C>T`, `NM_001331035.2:c.1399C>T`, `NM_001375278.1:c.1444C>T`, `NM_001375279.1:c.1420C>T`, `NM_001375280.1:c.1399C>T`, `NM_001375281.1:c.1420C>T`, `NM_001375282.1:c.1399C>T`, `NM_001375283.1:c.1363C>T`, `NM_001375284.1:c.811C>T`, `NR_164672.1:n.1470C>T`, `NR_164673.1:n.1444C>T`

## 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 4.239, GERP -0.612, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **nonsense (stop-gain)** — 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 11 of 13**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 44.0**. 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 **0.00439%** (sas) · FAF95 0.00153% · FAF99 0.0013% · 4/91,072 in the highest group · 35/1,613,566 alleles overall — very rare (popmax 0.00439%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0048% | 20,825 |
| South Asian (grpmax) | 0.00439% | 22,768 |
| European (non-Finnish) | 0.0022% | 45,382 |
| Admixed American | 0.00167% | 59,948 |
| African / African-American | 0.00134% | 74,756 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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 **474** 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/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-09-26.

**Submitter consensus:** conflicting (5 Pathogenic, 1 risk factor, 1 Likely pathogenic).

**Submission history:** 7 submissions (2004–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | risk factor | no assertion criteria provided | literature only | 2004-06-01 |
| PreventionGenetics, part of Exact Sciences | Likely pathogenic | criteria provided, single submitter | clinical testing | 2022-12-05 |
| Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre | Pathogenic | criteria provided, single submitter | clinical testing | 2025-09-10 |
| Genomenon, Inc, Genomenon, Inc | Pathogenic | criteria provided, single submitter | curation | 2025-09-26 |
| Mayo Clinic Laboratories, Mayo Clinic | Pathogenic | criteria provided, single submitter | clinical testing | 2025-01-31 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-05-17 |
| Department of Human Genetics, Hannover Medical School | Pathogenic | criteria provided, single submitter | clinical testing | 2024-09-04 |

## Associated conditions {#conditions}

[CFI-related disorder](https://sugi.bio/atlas/disease/cfi-related-disorder/), [complement factor I deficiency](https://sugi.bio/atlas/disease/complement-factor-i-deficiency/), [atypical hemolytic-uremic syndrome with I factor anomaly](https://sugi.bio/atlas/disease/atypical-hemolytic-uremic-syndrome-with-i-factor-anomaly/), [age related macular degeneration 13](https://sugi.bio/atlas/disease/age-related-macular-degeneration-13/).

**Reported phenotype names (ClinVar):** CFI-related disorder, Atypical hemolytic-uremic syndrome with I factor anomaly, not provided, Age related macular degeneration 13, Factor I deficiency, CFI-related disorders, CFI-related condition, Complement factor I deficiency, none provided, HEMOLYTIC UREMIC SYNDROME, ATYPICAL, SUSCEPTIBILITY TO, 3.

## Similar variants {#similar}

Related CFI variant pages (same residue, condition, or type): [CFI p.Arg474Gln](/variant/cfi-p-arg474gln), [CFI c.1429+1G>C](/variant/cfi-c-1429-plus-1g-c), [CFI c.57+1G>C](/variant/cfi-c-57-plus-1g-c), [CFI c.658+1G>A](/variant/cfi-c-658-plus-1g-a), [CFI c.905-1G>C](/variant/cfi-c-905-minus-1g-c), [CFI p.Ala258Thr](/variant/cfi-p-ala258thr), [CFI p.Arg187Ter](/variant/cfi-p-arg187ter), [CFI p.Trp145Ter](/variant/cfi-p-trp145ter).

### 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 12121). 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.*