# NM_000064.4(C3):c.1042A>G (p.Ile348Val)

https://sugi.bio/variant/c3-p-ile348val

## Summary

**C3 p.Ile348Val (c.1042A>G)** is classified **Conflicting classifications of pathogenicity** in C3 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-08-11). AlphaMissense: likely benign (0.1343); Very rare (popmax 0.00949%, nfe); Associated with complement component 3 deficiency.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs141737564 · 3 submitters · 3 linked conditions · AlphaMissense likely benign · very rare (popmax 0.00949%, 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 3 submitters, and is linked to complement component 3 deficiency.

*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 recessive |
| Age of onset (of this condition) | Childhood |
| 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/0016489/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.Ile348Val |
| Coding change (HGVS c.) | c.1042A>G |
| MANE Select transcript | [NM_000064](https://www.ncbi.nlm.nih.gov/nuccore/NM_000064) |
| dbSNP | [rs141737564](https://www.ncbi.nlm.nih.gov/snp/rs141737564/) |
| Variant type | single nucleotide variant |
| Location | chr19:6712585-6712585 (GRCh38) |
| ClinVar | [VCV330331](https://www.ncbi.nlm.nih.gov/clinvar/variation/330331/) |

**All HGVS expressions:** `LRG_27:g.13067A>G`, `LRG_27t1:c.1042A>G`, `NC_000019.10:g.6712585T>C`, `NC_000019.9:g.6712596T>C`, `NG_009557.1:g.13067A>G`, `NM_000064.4:c.1042A>G`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.1343)
- REVEL 0.148 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -8.17 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **acceptor loss** (Δ 0.30) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 7.666, GERP 1.75, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 23.7**. 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 0.74** across the covering region of the MANE Select transcript (6,684,600–6,719,350), spanning 34,750 bp. Chi-square p 3.5e-28. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.30**, donor loss **0.00**, acceptor gain **0.01**, donor gain **0.03**. Largest is acceptor loss.
- SpliceAI deltas (masked): acceptor loss **0.30**, donor loss **0.00**, acceptor gain **0.01**, donor gain **0.03**.
- Population frequency (gnomAD v4.1): grpmax **0.00949%** (nfe) · FAF95 0.00804% · FAF99 0.00752% · 112/1,179,990 in the highest group · 116/1,614,126 alleles overall — very rare (popmax 0.00949%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00949% | 10,536 |
| Remaining individuals (not grpmax-eligible) | 0.0064% | 15,626 |

*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 **348** 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-08-11.

**Submitter consensus:** conflicting (4 Uncertain significance, 1 Benign).

**Submission history:** 5 submissions (2019–2025); 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 | 2019-07-08 |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2019-07-08 |
| Mayo Clinic Laboratories, Mayo Clinic | Uncertain significance | criteria provided, single submitter | clinical testing | 2019-12-03 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-08-11 |

## Associated conditions {#conditions}

[complement component 3 deficiency](https://sugi.bio/atlas/disease/complement-component-3-deficiency/), [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/).

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

## Similar variants {#similar}

Related C3 variant pages (same residue, condition, or type): [C3 p.Ile348=](/variant/c3-p-ile348), [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 2026-10-11); 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 330331). 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.*