# NM_000186.4(CFH):c.921A>C (p.Ala307=)

https://sugi.bio/variant/cfh-p-ala307

## Summary

**CFH p.Ala307= (c.921A>C)** is classified **Benign/Likely benign** in CFH (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-02-04). Common (popmax 94.1%, eas) — too common for a highly-penetrant pathogenic allele; Associated with basal laminar drusen.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs1061147 · 10 submitters · 5 linked conditions · common (popmax 94.1%, eas) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the CFH gene that is classified as benign/likely benign — not considered disease-causing, submitted by 10 submitters, and is linked to basal laminar drusen.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015060/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.Ala307= |
| Coding change (HGVS c.) | c.921A>C |
| MANE Select transcript | [NM_000186](https://www.ncbi.nlm.nih.gov/nuccore/NM_000186) |
| dbSNP | [rs1061147](https://www.ncbi.nlm.nih.gov/snp/rs1061147/) |
| Variant type | single nucleotide variant |
| Location | chr1:196685194-196685194 (GRCh38) |
| ClinVar | [VCV294488](https://www.ncbi.nlm.nih.gov/clinvar/variation/294488/) |

**All HGVS expressions:** `LRG_47:g.38184A>C`, `LRG_47t1:c.921A>C`, `NC_000001.10:g.196654324A>C`, `NC_000001.11:g.196685194A>C`, `NG_007259.1:g.38184A>C`, `NM_000186.4:c.921A>C`, `NM_001014975.3:c.921A>C`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 94.1%, eas) — too common for a highly-penetrant pathogenic allele.

- **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 -0.346, GERP -3.48 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 3.942**. 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 **94.1%** (eas) · FAF95 93.3% · FAF99 93% · 42,152/44,802 in the highest group · 1,022,671/1,612,176 alleles overall — common (popmax 94.1%, eas) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 94.1% | 1 |
| Admixed American | 79.8% | 1 |
| South Asian | 69.6% | 1 |
| Ashkenazi Jewish (not grpmax-eligible) | 65.5% | 2 |
| Remaining individuals (not grpmax-eligible) | 64.1% | 2 |
| Middle Eastern | 63.2% | 2 |
| European (non-Finnish) | 61.7% | 2 |
| African / African-American | 57.8% | 2 |
| Finnish (not grpmax-eligible) | 56% | 2 |
| Amish (not grpmax-eligible) | 52% | 2 |

*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 **307** lies in a disulfide bond; the sushi 5 domain.

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.Ala307= falls in the sushi 5 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}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-04.

**Submitter consensus:** conflicting (15 Benign, 1 Likely benign).

**Submission history:** 16 submissions (2017–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genome Diagnostics Laboratory, The Hospital for Sick Children | Benign | criteria provided, single submitter | clinical testing | 2022-10-05 |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2021-05-04 |
| Genome-Nilou Lab | Benign | criteria provided, single submitter | clinical testing | 2021-07-22 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Benign | criteria provided, single submitter | clinical testing | 2026-01-21 |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2017-04-27 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| Genomenon, Inc, Genomenon, Inc | Benign | criteria provided, single submitter | curation | 2025-10-02 |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | criteria provided, single submitter | clinical testing | 2022-09-09 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-04 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-26 |

## Associated conditions {#conditions}

[basal laminar drusen](https://sugi.bio/atlas/disease/basal-laminar-drusen/), [hemolytic uremic syndrome, atypical, susceptibility to, 1](https://sugi.bio/atlas/disease/hemolytic-uremic-syndrome-atypical-susceptibility-to-1/), [complement factor H deficiency](https://sugi.bio/atlas/disease/complement-factor-h-deficiency/), [age related macular degeneration 4](https://sugi.bio/atlas/disease/age-related-macular-degeneration-4/), [atypical hemolytic-uremic syndrome](https://sugi.bio/atlas/disease/atypical-hemolytic-uremic-syndrome/).

**Reported phenotype names (ClinVar):** Basal laminar drusen, Age related macular degeneration 4, CFH-Related Dense Deposit Disease / Membranoproliferative Glomerulonephritis Type II, Hemolytic uremic syndrome, atypical, susceptibility to, 1, not provided, Factor H deficiency, Atypical hemolytic-uremic syndrome, not specified, DRUSEN OF BRUCH MEMBRANE, DRUSEN, CUTICULAR.

## 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 294488). 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.*