# NM_000186.4(CFH):c.1864A>G (p.Ile622Val)

https://sugi.bio/variant/cfh-p-ile622val

## Summary

**CFH p.Ile622Val (c.1864A>G)** is classified **Uncertain significance** in CFH (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-10-02). AlphaMissense: likely benign (0.0725); Very rare (popmax 0.00333%, amr); Associated with age related macular degeneration 4.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs990484984 · 6 submitters · 5 linked conditions · AlphaMissense likely benign · very rare (popmax 0.00333%, amr)

## 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 6 submitters, and is linked to age related macular degeneration 4.

*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.*

|  |  |
| --- | --- |
| Diagnostic panels | CFH is a diagnostic-grade gene on 7 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0024872/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.Ile622Val |
| Coding change (HGVS c.) | c.1864A>G |
| MANE Select transcript | [NM_000186](https://www.ncbi.nlm.nih.gov/nuccore/NM_000186) |
| dbSNP | [rs990484984](https://www.ncbi.nlm.nih.gov/snp/rs990484984/) |
| Variant type | single nucleotide variant |
| Location | chr1:196725288-196725288 (GRCh38) |
| ClinVar | [VCV1163676](https://www.ncbi.nlm.nih.gov/clinvar/variation/1163676/) |

**All HGVS expressions:** `LRG_47:g.78278A>G`, `LRG_47t1:c.1864A>G`, `NC_000001.10:g.196694418A>G`, `NC_000001.11:g.196725288A>G`, `NG_007259.1:g.78278A>G`, `NM_000186.4:c.1864A>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0725)
- REVEL 0.092 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -5.641 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **donor gain** (Δ 0.33) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 2.794, GERP -0.712, phastCons 0.004 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 15.69**. 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 1.01** across the covering region of the MANE Select transcript (196,690,101–196,743,557), spanning 53,456 bp. Chi-square p 0.76. 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 **0.33**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.33**.
- Population frequency (gnomAD v4.1): grpmax **0.00333%** (amr) · FAF95 0.000553% · FAF99 0.000207% · 2/59,974 in the highest group · 8/1,613,544 alleles overall — very rare (popmax 0.00333%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00333% | 29,987 |
| European (non-Finnish) | 0.000509% | 196,610 |

*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 **622** lies in the sushi 10 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.Ile622Val falls in the sushi 10 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 Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-10-02.

**Submitter consensus:** unanimous (9/9 Uncertain significance).

**Submission history:** 9 submissions (2020–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Mayo Clinic Laboratories, Mayo Clinic | Uncertain significance | criteria provided, single submitter | clinical testing | 2020-02-05 |
| Genome-Nilou Lab | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-04-11 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-06-02 |
| Genomenon, Inc, Genomenon, Inc | Uncertain significance | criteria provided, single submitter | curation | 2025-10-02 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-08-02 |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-06-06 |

## Associated conditions {#conditions}

[age related macular degeneration 4](https://sugi.bio/atlas/disease/age-related-macular-degeneration-4/), [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/), [atypical hemolytic-uremic syndrome](https://sugi.bio/atlas/disease/atypical-hemolytic-uremic-syndrome/).

**Reported phenotype names (ClinVar):** Age related macular degeneration 4, not provided, Hemolytic uremic syndrome, atypical, susceptibility to, 1, Factor H deficiency, Basal laminar drusen, not specified, Atypical hemolytic-uremic syndrome, AllHighlyPenetrant, none provided, DRUSEN OF BRUCH MEMBRANE.

## 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 1163676). 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.*