# NM_000186.4(CFH):c.2689T>C (p.Leu897=)

https://sugi.bio/variant/cfh-p-leu897

## Summary

**CFH p.Leu897= (c.2689T>C)** is classified **Likely benign** in CFH (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-15). Very rare (popmax 0.00167%, amr).

**At a glance:** Likely benign · review: Single submitter · rsID rs1313218518 · 1 submitter · very rare (popmax 0.00167%, amr)

## For patients & families {#patients}

This is a change in the CFH gene that is classified as likely benign — not considered disease-causing, 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 | [CFH](https://sugi.bio/atlas/gene/CFH/) |
| Protein change (HGVS p.) | p.Leu897= |
| Coding change (HGVS c.) | c.2689T>C |
| MANE Select transcript | [NM_000186](https://www.ncbi.nlm.nih.gov/nuccore/NM_000186) |
| dbSNP | [rs1313218518](https://www.ncbi.nlm.nih.gov/snp/rs1313218518/) |
| Variant type | single nucleotide variant |
| Location | chr1:196737567-196737567 (GRCh38) |
| ClinVar | [VCV2110759](https://www.ncbi.nlm.nih.gov/clinvar/variation/2110759/) |

**All HGVS expressions:** `LRG_47:g.90557T>C`, `LRG_47t1:c.2689T>C`, `NC_000001.10:g.196706697T>C`, `NC_000001.11:g.196737567T>C`, `NG_007259.1:g.90557T>C`, `NM_000186.4:c.2689T>C`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **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 -3.451, GERP -3.67 — fast-evolving / accelerated position
- CADD: **PHRED 1.324**. 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: **below the reporting threshold**. This position is scored for a different substitution (T>G, Δ0.24 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00167%** (amr) · 1/59,984 in the highest group · 1/1,461,088 alleles overall — very rare (popmax 0.00167%, amr).

*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 **897** lies in the sushi 15 domain; a β-strand; 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.Leu897= falls in the sushi 15 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}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-05-15.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-05-15 |

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

## Similar variants {#similar}

Related CFH variant pages (same residue, condition, or type): [CFH c.1337-2A>G](/variant/cfh-c-1337-minus-2a-g), [CFH c.1520-1G>A](/variant/cfh-c-1520-minus-1g-a), [CFH c.2236+1G>C](/variant/cfh-c-2236-plus-1g-c), [CFH c.3493+1G>A](/variant/cfh-c-3493-plus-1g-a), [CFH c.350+1G>T](/variant/cfh-c-350-plus-1g-t), [CFH c.619+1G>A](/variant/cfh-c-619-plus-1g-a), [CFH p.Arg1215Leu](/variant/cfh-p-arg1215leu), [CFH p.Arg1215Ter](/variant/cfh-p-arg1215ter).

### 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 2110759). 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.*