# NM_000064.4(C3):c.2421G>C (p.Val807=)

https://sugi.bio/variant/c3-p-val807

## Summary

**C3 p.Val807= (c.2421G>C)** is classified **Benign/Likely benign** in C3 (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-02-04). Common (popmax 86.3%, eas) — too common for a highly-penetrant pathogenic allele; Associated with age related macular degeneration 9.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs428453 · 10 submitters · 5 linked conditions · common (popmax 86.3%, eas) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the C3 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 10 submitters, and is linked to age related macular degeneration 9.

*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 | C3 is a diagnostic-grade gene on 7 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0024877/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [C3](https://sugi.bio/atlas/gene/C3/) |
| Protein change (HGVS p.) | p.Val807= |
| Coding change (HGVS c.) | c.2421G>C |
| MANE Select transcript | [NM_000064](https://www.ncbi.nlm.nih.gov/nuccore/NM_000064) |
| dbSNP | [rs428453](https://www.ncbi.nlm.nih.gov/snp/rs428453/) |
| Variant type | single nucleotide variant |
| Location | chr19:6702146-6702146 (GRCh38) |
| ClinVar | [VCV330305](https://www.ncbi.nlm.nih.gov/clinvar/variation/330305/) |

**All HGVS expressions:** `LRG_27:g.23506G>C`, `LRG_27t1:c.2421G>C`, `NC_000019.10:g.6702146C>G`, `NC_000019.9:g.6702157C>G`, `NG_009557.1:g.23506G>C`, `NM_000064.4:c.2421G>C`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 86.3%, 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 0.282, GERP 0.709, phastCons 0.987 — weakly conserved position
- CADD: **PHRED 7.198**. 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: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for C3 (1,625 scored positions, the nearest 3 bases away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency (gnomAD v4.1): grpmax **86.3%** (eas) · FAF95 85.5% · FAF99 85.2% · 38,635/44,786 in the highest group · 1,018,866/1,595,750 alleles overall — common (popmax 86.3%, eas) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 86.3% | 1 |
| Admixed American | 78.4% | 1 |
| African / African-American | 70.8% | 1 |
| South Asian | 70.7% | 1 |
| Middle Eastern | 67.3% | 1 |
| Remaining individuals (not grpmax-eligible) | 64.9% | 2 |
| European (non-Finnish) | 61.7% | 2 |
| Ashkenazi Jewish (not grpmax-eligible) | 59.4% | 2 |
| Finnish (not grpmax-eligible) | 56.6% | 2 |
| Amish (not grpmax-eligible) | 44.4% | 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}

**C3** population constraint: LOEUF 0.541, pLI 1.2692e-06, missense-Z 4.4464. *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** — Moderate (AD)
- **atypical hemolytic-uremic syndrome with C3 anomaly** — Definitive (AD)

## Protein context {#protein}

Residue **807** lies in a β-strand.

AlphaFold model confidence (whole protein): pLDDT 79.84, 23% of residues very-high.

**80 experimental structure(s)** (PDB): [11MG](https://www.rcsb.org/structure/11MG), [11MH](https://www.rcsb.org/structure/11MH), [1C3D](https://www.rcsb.org/structure/1C3D), [1GHQ](https://www.rcsb.org/structure/1GHQ), [1W2S](https://www.rcsb.org/structure/1W2S), [2A73](https://www.rcsb.org/structure/2A73) — incl. mutant structure 3RJ3.

## What this gene does {#gene-function}

*Describes the biological roles of C3 (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:** C3's established molecular role includes C5L2 anaphylatoxin chemotactic receptor binding. In Reactome, C3 is annotated in disease pathway(s) including **Purinergic signaling in leishmaniasis infection**.

**Disease mechanism (Reactome):** C3 loss or alteration is curated in [Purinergic signaling in leishmaniasis infection](https://reactome.org/content/detail/R-HSA-9660826).

### Pathways affected {#pathways}

C3 participates in **11 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Purinergic signaling in leishmaniasis infection](https://reactome.org/content/detail/R-HSA-9660826) | curated |
| [Activation of C3 and C5](https://reactome.org/content/detail/R-HSA-174577) | curated |
| [Alternative complement activation](https://reactome.org/content/detail/R-HSA-173736) | curated |
| [G alpha (i) signalling events](https://reactome.org/content/detail/R-HSA-418594) | curated |
| [Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell](https://reactome.org/content/detail/R-HSA-198933) | curated |
| [Neutrophil degranulation](https://reactome.org/content/detail/R-HSA-6798695) | curated |
| [Peptide ligand-binding receptors](https://reactome.org/content/detail/R-HSA-375276) | curated |
| [Post-translational protein phosphorylation](https://reactome.org/content/detail/R-HSA-8957275) | curated |
| [Regulation of Complement cascade](https://reactome.org/content/detail/R-HSA-977606) | curated |
| [Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)](https://reactome.org/content/detail/R-HSA-381426) | curated |
| [Affinity selection of immunoglobulins](https://reactome.org/content/detail/R-HSA-9938027) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** C5L2 anaphylatoxin chemotactic receptor binding, receptor ligand activity.

**Biological process:** positive regulation of protein phosphorylation, complement activation, positive regulation of vascular endothelial growth factor production, positive regulation of D-glucose transmembrane transport, regulation of triglyceride biosynthetic process, positive regulation of lipid storage.

## Clinical significance {#significance}

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

**Submitter consensus:** conflicting (12 Benign, 1 Likely benign).

**Submission history:** 13 submissions (2018–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-01-12 |
| Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | Benign | no assertion criteria provided | clinical testing |  |
| Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | Benign | no assertion criteria provided | clinical testing |  |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-28 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| Genome-Nilou Lab | Benign | criteria provided, single submitter | clinical testing | 2021-07-14 |
| Genomenon, Inc, Genomenon, Inc | Benign | criteria provided, single submitter | curation | 2025-09-30 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Benign | criteria provided, single submitter | clinical testing | 2026-01-21 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-04 |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | criteria provided, single submitter | clinical testing | 2022-03-10 |

## Associated conditions {#conditions}

[age related macular degeneration 9](https://sugi.bio/atlas/disease/age-related-macular-degeneration-9/), [atypical hemolytic-uremic syndrome with C3 anomaly](https://sugi.bio/atlas/disease/atypical-hemolytic-uremic-syndrome-with-c3-anomaly/), [complement component 3 deficiency](https://sugi.bio/atlas/disease/complement-component-3-deficiency/), [C3 glomerulonephritis](https://sugi.bio/atlas/disease/c3-glomerulonephritis/), [atypical hemolytic-uremic syndrome](https://sugi.bio/atlas/disease/atypical-hemolytic-uremic-syndrome/).

**Reported phenotype names (ClinVar):** Age related macular degeneration 9, Atypical hemolytic-uremic syndrome with C3 anomaly, Complement component 3 deficiency, not specified, not provided, Atypical hemolytic-uremic syndrome, C3 glomerulonephritis, none provided, AHUS, SUSCEPTIBILITY TO, 5, C3 GLOMERULOPATHY 3.

## Similar variants {#similar}

Related C3 variant pages (same residue, condition, or type): [C3 c.1003+1G>A](/variant/c3-c-1003-plus-1g-a), [C3 c.2863+1G>T](/variant/c3-c-2863-plus-1g-t), [C3 c.4030-2A>G](/variant/c3-c-4030-minus-2a-g), [C3 p.Arg161Trp](/variant/c3-p-arg161trp), [C3 p.Arg592Gln](/variant/c3-p-arg592gln), [C3 p.Arg592Trp](/variant/c3-p-arg592trp), [C3 p.Arg764Ter](/variant/c3-p-arg764ter), [C3 p.Ile1157Thr](/variant/c3-p-ile1157thr).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 2026-10-14); 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 330305). 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.*