# NM_000204.5(CFI):c.1354G>C (p.Ala452Pro)

https://sugi.bio/variant/cfi-p-ala452pro

## Summary

**CFI p.Ala452Pro (c.1354G>C)** is classified **Likely pathogenic** in CFI (ClinVar, Single submitter, 1 submitter; last evaluated 2026-09-17). AlphaMissense: likely pathogenic (0.9013); Very rare (popmax 0.00133%, afr); Associated with atypical hemolytic-uremic syndrome.

**At a glance:** Likely pathogenic · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 0.00133%, afr)

## For patients & families {#patients}

This is a change in the CFI gene that is considered likely disease-causing, submitted by 1 submitter, 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 | CFI is a diagnostic-grade gene on 6 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 | [CFI](https://sugi.bio/atlas/gene/CFI/) |
| Protein change (HGVS p.) | p.Ala452Pro |
| Coding change (HGVS c.) | c.1354G>C |
| MANE Select transcript | [NM_000204](https://www.ncbi.nlm.nih.gov/nuccore/NM_000204) |
| Variant type | single nucleotide variant |
| Location | chr4:109746297-109746297 (GRCh38) |
| ClinVar | [VCV4280431](https://www.ncbi.nlm.nih.gov/clinvar/variation/4280431/) |

**All HGVS expressions:** `LRG_48:g.60689G>C`, `LRG_48t1:c.1354G>C`, `NC_000004.11:g.110667453C>G`, `NC_000004.12:g.109746297C>G`, `NG_007569.1:g.60689G>C`, `NM_000204.5:c.1354G>C`, `NM_001318057.2:c.1378G>C`, `NM_001331035.2:c.1333G>C`, `NM_001375278.1:c.1378G>C`, `NM_001375279.1:c.1354G>C`, `NM_001375280.1:c.1333G>C`, `NM_001375281.1:c.1354G>C`, `NM_001375282.1:c.1333G>C`, `NM_001375283.1:c.1297G>C`, `NM_001375284.1:c.745G>C`, `NM_001440985.1:c.1375G>C`, `NM_001440986.1:c.1375G>C`, `NM_001440988.1:c.1378G>C`, `NM_001440989.1:c.1354G>C`, `NM_001440991.1:c.1333G>C`, `NR_164672.1:n.1404G>C`, `NR_164673.1:n.1378G>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9013) — concordant with the pathogenic call
- REVEL 0.88 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -9.558 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense and REVEL call this damaging; SaProt does not
- SpliceAI predicts **donor gain** (Δ 0.27) — consistent with the pathogenic call
- Conservation: phyloP 5.904, GERP 1.74, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 28.3**. 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.*
- Regional missense constraint: **o/e 1.00** across the covering region of the MANE Select transcript (109,740,896–109,801,971), spanning 61,075 bp. Chi-square p 0.95. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.27**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.27**.
- Population frequency (gnomAD v4.1): grpmax **0.00133%** (afr) · 1/74,920 in the highest group · 2/1,614,026 alleles overall — very rare (popmax 0.00133%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00133% | 74,920 |
| European (non-Finnish) | 8.47e-05% | 1,180,020 |

*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 **452** lies in an α-helix; 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}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2026-09-17.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genomenon, Inc, Genomenon, Inc | Likely pathogenic | criteria provided, single submitter | curation | 2026-09-17 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Atypical hemolytic-uremic syndrome.

## Similar variants {#similar}

Related CFI variant pages (same residue, condition, or type): [CFI p.Ala452Ser](/variant/cfi-p-ala452ser), [CFI p.Ala452Thr](/variant/cfi-p-ala452thr), [CFI p.Ala452=](/variant/cfi-p-ala452), [CFI p.Ala452Asp](/variant/cfi-p-ala452asp), [CFI c.1429+1G>C](/variant/cfi-c-1429-plus-1g-c), [CFI p.Ala384Thr](/variant/cfi-p-ala384thr), [CFI p.Arg168Gly](/variant/cfi-p-arg168gly), [CFI p.Arg389His](/variant/cfi-p-arg389his).

### 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 4280431). 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.*