# NM_000064.4(C3):c.2067G>A (p.Glu689=)

https://sugi.bio/variant/c3-p-glu689

## Summary

**C3 p.Glu689= (c.2067G>A)** is classified **Conflicting classifications of pathogenicity** in C3 (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2026-04-01). Rare (popmax 0.187%, nfe); Associated with atypical hemolytic-uremic syndrome.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs147477257 · 9 submitters · 4 linked conditions · rare (popmax 0.187%, nfe)

## 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 9 submitters, and is linked to atypical hemolytic-uremic syndrome.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant, Autosomal recessive, Not applicable |
| Age of onset (of this condition) | All ages |
| Prevalence | 1-9 / 1 000 000 (United States) |
| Clinical trials | 40 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | C3 is a diagnostic-grade gene on 7 Genomics England panels |

**Commonly reported features of Atypical hemolytic uremic syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Proteinuria — Very frequent (99-80%)
- Hematuria — Very frequent (99-80%)
- Abnormality of blood and blood-forming tissues — Very frequent (99-80%)
- Thrombocytopenia — Very frequent (99-80%)
- Acute kidney injury — Very frequent (99-80%)
- Microangiopathic hemolytic anemia — Very frequent (99-80%)
- Abnormality of metabolism/homeostasis — Very frequent (99-80%)
- Abnormal lactate dehydrogenase activity — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0008702/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.Glu689= |
| Coding change (HGVS c.) | c.2067G>A |
| MANE Select transcript | [NM_000064](https://www.ncbi.nlm.nih.gov/nuccore/NM_000064) |
| dbSNP | [rs147477257](https://www.ncbi.nlm.nih.gov/snp/rs147477257/) |
| Variant type | single nucleotide variant |
| Location | chr19:6707254-6707254 (GRCh38) |
| ClinVar | [VCV330312](https://www.ncbi.nlm.nih.gov/clinvar/variation/330312/) |

**All HGVS expressions:** `LRG_27:g.18398G>A`, `LRG_27t1:c.2067G>A`, `NC_000019.10:g.6707254C>T`, `NC_000019.9:g.6707265C>T`, `NG_009557.1:g.18398G>A`, `NM_000064.4:c.2067G>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 (below), not from a missing predictor score.
- Conservation: phyloP -0.183, GERP -1.78 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 3.888**. 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 **0.187%** (nfe) · FAF95 0.18% · FAF99 0.178% · 2,202/1,179,052 in the highest group · 2,309/1,611,634 alleles overall — rare (popmax 0.187%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.187% | 535 |
| Remaining individuals (not grpmax-eligible) | 0.0833% | 1,200 |
| Finnish (not grpmax-eligible) | 0.0409% | 2,448 |
| African / African-American | 0.0361% | 2,769 |
| Admixed American | 0.00335% | 29,819 |

*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 **689** lies in an α-helix; a disulfide bond.

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 2026-04-01.

**Submitter consensus:** conflicting (9 Likely benign, 1 Uncertain significance, 1 Benign).

**Submission history:** 11 submissions (2018–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Likely benign | criteria provided, single submitter | clinical testing | 2018-01-12 |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-12 |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-01-12 |
| Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | Likely benign | no assertion criteria provided | clinical testing |  |
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Likely benign | no assertion criteria provided | clinical testing |  |
| Genome Diagnostics Laboratory, The Hospital for Sick Children | Likely benign | criteria provided, single submitter | clinical testing | 2020-05-01 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2026-04-01 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-10-25 |
| Genome Diagnostics Laboratory, University Medical Center Utrecht | Likely benign | no assertion criteria provided | clinical testing |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-12-08 |
| Mayo Clinic Laboratories, Mayo Clinic | Likely benign | criteria provided, single submitter | clinical testing | 2025-09-17 |

## Associated conditions {#conditions}

[atypical hemolytic-uremic syndrome](https://sugi.bio/atlas/disease/atypical-hemolytic-uremic-syndrome/), [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):** Atypical hemolytic-uremic syndrome, Complement component 3 deficiency, Atypical hemolytic-uremic syndrome with C3 anomaly, Age related macular degeneration 9, not provided, not specified, none provided, AHUS, SUSCEPTIBILITY TO, 5, AllHighlyPenetrant.

## 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 2026-10-11); 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 330312). 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.*