# NM_000064.4(C3):c.2799G>A (p.Pro933=)

https://sugi.bio/variant/c3-p-pro933

## Summary

**C3 p.Pro933= (c.2799G>A)** is classified **Conflicting classifications of pathogenicity** in C3 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-23). Rare (popmax 0.231%, mid); Associated with atypical hemolytic-uremic syndrome with C3 anomaly.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs149209011 · 3 submitters · 3 linked conditions · rare (popmax 0.231%, mid)

## For patients & families {#patients}

This is a change in the C3 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 3 submitters, and is linked to atypical hemolytic-uremic syndrome with C3 anomaly.

*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/0018555/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.Pro933= |
| Coding change (HGVS c.) | c.2799G>A |
| MANE Select transcript | [NM_000064](https://www.ncbi.nlm.nih.gov/nuccore/NM_000064) |
| dbSNP | [rs149209011](https://www.ncbi.nlm.nih.gov/snp/rs149209011/) |
| Variant type | single nucleotide variant |
| Location | chr19:6696657-6696657 (GRCh38) |
| ClinVar | [VCV330299](https://www.ncbi.nlm.nih.gov/clinvar/variation/330299/) |

**All HGVS expressions:** `LRG_27:g.28995G>A`, `LRG_27t1:c.2799G>A`, `NC_000019.10:g.6696657C>T`, `NC_000019.9:g.6696668C>T`, `NG_009557.1:g.28995G>A`, `NM_000064.4:c.2799G>A`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor gain** (Δ 0.80) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -15, GERP -3.17 — fast-evolving / accelerated position
- CADD: **PHRED 12.82**. 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 deltas (raw): acceptor loss **0.04**, donor loss **0.00**, acceptor gain **0.80**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.04**, donor loss **0.00**, acceptor gain **0.80**, donor gain **0.00**.
- Pangolin: Δ**0.41** (gain), gain 0.41 / loss 0.10. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.231%** (mid) · FAF95 0.14% · FAF99 0.112% · 14/6,062 in the highest group · 154/1,613,848 alleles overall — rare (popmax 0.231%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.231% | 433 |
| African / African-American | 0.0934% | 1,071 |
| Remaining individuals (not grpmax-eligible) | 0.0208% | 4,807 |
| Admixed American | 0.0167% | 5,999 |
| European (non-Finnish) | 0.0039% | 25,649 |
| East Asian | 0.00223% | 44,864 |

*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}


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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-12-23.

**Submitter consensus:** conflicting (2 Uncertain significance, 2 Benign, 1 Likely benign).

**Submission history:** 5 submissions (2018–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2025-12-23 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-14 |

## Associated conditions {#conditions}

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

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

## Similar variants {#similar}

Related C3 variant pages (same residue, condition, or type): [C3 p.Pro933Leu](/variant/c3-p-pro933leu), [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).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 330299). 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.*