# NM_001737.5(C9):c.1518T>C (p.Ser506=)

https://sugi.bio/variant/c9-p-ser506

## Summary

**C9 p.Ser506= (c.1518T>C)** is classified **Likely benign** in C9 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-10). Very rare (popmax 0.000425%, nfe).

**At a glance:** Likely benign · review: Single submitter · rsID rs1305232962 · 1 submitter · very rare (popmax 0.000425%, nfe)

## For patients & families {#patients}

This is a change in the C9 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter.

*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:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [C9](https://sugi.bio/atlas/gene/C9/) |
| Protein change (HGVS p.) | p.Ser506= |
| Coding change (HGVS c.) | c.1518T>C |
| MANE Select transcript | [NM_001737](https://www.ncbi.nlm.nih.gov/nuccore/NM_001737) |
| dbSNP | [rs1305232962](https://www.ncbi.nlm.nih.gov/snp/rs1305232962/) |
| Variant type | single nucleotide variant |
| Location | chr5:39288850-39288850 (GRCh38) |
| ClinVar | [VCV3011185](https://www.ncbi.nlm.nih.gov/clinvar/variation/3011185/) |

**All HGVS expressions:** `LRG_32:g.80704T>C`, `LRG_32t1:c.1518T>C`, `NC_000005.10:g.39288850A>G`, `NC_000005.9:g.39288952A>G`, `NG_009894.1:g.80704T>C`, `NM_001737.5:c.1518T>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 1.49, GERP -3.12 — weakly conserved position
- CADD: **PHRED 5.924**. 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 (A>C, Δ0.78 donor 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 **0.000425%** (nfe) · FAF95 0.000124% · FAF99 9e-05% · 5/1,177,654 in the highest group · 5/1,610,910 alleles overall — very rare (popmax 0.000425%, nfe).

*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}

**C9** population constraint: LOEUF 1.223, pLI 4.8359e-12, missense-Z -0.66282. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **506** lies in the macpf domain.

AlphaFold model confidence (whole protein): pLDDT 79.32, 40% of residues very-high.

**9 experimental structure(s)** (PDB): [5FMW](https://www.rcsb.org/structure/5FMW), [6DLW](https://www.rcsb.org/structure/6DLW), [6H03](https://www.rcsb.org/structure/6H03), [6H04](https://www.rcsb.org/structure/6H04), [7NYC](https://www.rcsb.org/structure/7NYC), [7NYD](https://www.rcsb.org/structure/7NYD).

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

*Describes the biological roles of C9 (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.*


### Pathways affected {#pathways}

C9 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Regulation of Complement cascade](https://reactome.org/content/detail/R-HSA-977606) | curated |
| [Terminal pathway of complement](https://reactome.org/content/detail/R-HSA-166665) | curated |

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

**Biological process:** cell killing, complement activation, killing of cells of another organism, protein homooligomerization, complement activation, GZMK pathway.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-08-10.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2023-08-10 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related C9 variant pages (same residue, condition, or type): [C9 c.871-2A>G](/variant/c9-c-871-minus-2a-g), [C9 p.Arg116Ter](/variant/c9-p-arg116ter), [C9 p.Arg154Ter](/variant/c9-p-arg154ter), [C9 p.Arg194Ter](/variant/c9-p-arg194ter), [C9 p.Arg86Ter](/variant/c9-p-arg86ter), [C9 p.Cys54Ter](/variant/c9-p-cys54ter), [C9 c.1240+5G>T](/variant/c9-c-1240-plus-5g-t), [C9 p.Ala497Val](/variant/c9-p-ala497val).

### 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 3011185). 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.*