# NM_000186.4(CFH):c.158G>C (p.Arg53Pro)

https://sugi.bio/variant/cfh-p-arg53pro

## Summary

**CFH p.Arg53Pro (c.158G>C)** is classified **Uncertain significance** in CFH (ClinVar, Single submitter, 1 submitter; last evaluated 2026-09-17). AlphaMissense: likely pathogenic (0.9291); Absent from gnomAD v4.1; Associated with atypical hemolytic-uremic syndrome.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the CFH gene that is currently of uncertain significance — a definitive interpretation has not yet been established, 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 | 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.Arg53Pro |
| Coding change (HGVS c.) | c.158G>C |
| MANE Select transcript | [NM_000186](https://www.ncbi.nlm.nih.gov/nuccore/NM_000186) |
| Variant type | single nucleotide variant |
| Location | chr1:196673077-196673077 (GRCh38) |
| ClinVar | [VCV4291425](https://www.ncbi.nlm.nih.gov/clinvar/variation/4291425/) |

**All HGVS expressions:** `LRG_47:g.26067G>C`, `LRG_47t1:c.158G>C`, `NC_000001.10:g.196642207G>C`, `NC_000001.11:g.196673077G>C`, `NG_007259.1:g.26067G>C`, `NM_000186.4:c.158G>C`, `NM_001014975.3:c.158G>C`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.9291)
- REVEL 0.435 (indeterminate)
- SaProt LLR -10.414 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL makes no call
- SpliceAI predicts **donor loss** (Δ 0.22) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 0.864, GERP -0.586, phastCons 0.203 — weakly conserved position
- AlphaMissense ranks this among the **top 8%** most-pathogenic-predicted substitutions in CFH (of 7,182 modeled).
- CADD: **PHRED 22.7**. 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 0.99** across the covering region of the MANE Select transcript (196,652,118–196,679,651), spanning 27,533 bp. Chi-square p 0.84. 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 **0.22**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss, 34 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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 **53** lies in the sushi 1 domain; a disulfide bond.

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.Arg53Pro falls in the sushi 1 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}

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

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genomenon, Inc, Genomenon, Inc | Uncertain significance | 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.

## Same-residue context {#hotspot}

Residue **53** carries **2 other pathogenic ClinVar variants** — a recurrently-mutated position: [CFH p.Arg53Cys](/variant/cfh-p-arg53cys), [CFH p.Arg53Ser](/variant/cfh-p-arg53ser). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related CFH variant pages (same residue, condition, or type): [CFH p.Arg53Cys](/variant/cfh-p-arg53cys), [CFH p.Arg53Ser](/variant/cfh-p-arg53ser), [CFH p.Arg53Gly](/variant/cfh-p-arg53gly), [CFH p.Arg53His](/variant/cfh-p-arg53his), [CFH p.Arg53Leu](/variant/cfh-p-arg53leu), [CFH p.Arg53=](/variant/cfh-p-arg53), [CFH c.1520-1G>A](/variant/cfh-c-1520-minus-1g-a), [CFH c.3493+1G>A](/variant/cfh-c-3493-plus-1g-a).

### 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 4291425). 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.*