# NM_000064.4(C3):c.1047G>C (p.Val349=)

https://sugi.bio/variant/c3-p-val349

## Summary

**C3 p.Val349= (c.1047G>C)** is classified **Likely benign** in C3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-11-25). Ultra-rare (popmax 0.015%, amr); Associated with age related macular degeneration 9.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs747191565 · 2 submitters · 3 linked conditions · ultra-rare (popmax 0.015%, amr)

## For patients & families {#patients}

This is a change in the C3 gene that is classified as likely benign — not considered disease-causing, submitted by 2 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.Val349= |
| Coding change (HGVS c.) | c.1047G>C |
| MANE Select transcript | [NM_000064](https://www.ncbi.nlm.nih.gov/nuccore/NM_000064) |
| dbSNP | [rs747191565](https://www.ncbi.nlm.nih.gov/snp/rs747191565/) |
| Variant type | single nucleotide variant |
| Location | chr19:6712580-6712580 (GRCh38) |
| ClinVar | [VCV1580979](https://www.ncbi.nlm.nih.gov/clinvar/variation/1580979/) |

**All HGVS expressions:** `LRG_27:g.13072G>C`, `NC_000019.10:g.6712580C>G`, `NC_000019.9:g.6712591C>G`, `NG_009557.1:g.13072G>C`, `NM_000064.4:c.1047G>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 -1.221, GERP -3.49 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 8.931**. 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 (C>A, Δ0.30 acceptor 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 **0.015%** (amr) · FAF95 0.00773% · FAF99 0.00578% · 9/60,004 in the highest group · 19/1,614,010 alleles overall — ultra-rare (popmax 0.015%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.015% | 6,667 |
| Remaining individuals (not grpmax-eligible) | 0.0048% | 20,828 |
| European (non-Finnish) | 0.000593% | 168,571 |

*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 **349** 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}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2023-11-25.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 2 submissions (2022–2023); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Fulgent Genetics, Fulgent Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2022-03-05 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2023-11-25 |

## 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/).

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

## 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 c.683-3C>A](/variant/c3-c-683-minus-3c-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 1580979). 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.*