# NM_000063.6(C2):c.2127T>C (p.Ala709=)

https://sugi.bio/variant/c2-p-ala709

## Summary

**C2 p.Ala709= (c.2127T>C)** is classified **Likely benign** in C2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-19). Very rare (popmax 0.004%, afr).

**At a glance:** Likely benign · review: Single submitter · rsID rs2482651792 · 1 submitter · very rare (popmax 0.004%, afr)

## For patients & families {#patients}

This is a change in the C2 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 | [C2](https://sugi.bio/atlas/gene/C2/) |
| Protein change (HGVS p.) | p.Ala709= |
| Coding change (HGVS c.) | c.2127T>C |
| MANE Select transcript | [NM_000063](https://www.ncbi.nlm.nih.gov/nuccore/NM_000063) |
| dbSNP | [rs2482651792](https://www.ncbi.nlm.nih.gov/snp/rs2482651792/) |
| Variant type | single nucleotide variant |
| Location | chr6:31945225-31945225 (GRCh38) |
| ClinVar | [VCV2807544](https://www.ncbi.nlm.nih.gov/clinvar/variation/2807544/) |

**All HGVS expressions:** `LRG_136:g.4282T>C`, `LRG_26:g.22737T>C`, `LRG_26t1:c.2127T>C`, `NC_000006.11:g.31913002T>C`, `NC_000006.12:g.31945225T>C`, `NG_008191.1:g.4282T>C`, `NG_011730.1:g.22737T>C`, `NM_000063.6:c.2127T>C`, `NM_001145903.3:c.1731T>C`, `NM_001178063.3:c.1485T>C`, `NM_001282457.2:c.1389T>C`, `NM_001282458.2:c.2040T>C`, `NR_073063.1:n.1610T>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 -4.082, GERP -3.49 — fast-evolving / accelerated position
- CADD: **PHRED 4.987**. 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 (T>A, Δ0.25 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 **0.004%** (afr) · FAF95 0.00106% · FAF99 0.000495% · 3/74,990 in the highest group · 5/1,612,944 alleles overall — very rare (popmax 0.004%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.004% | 24,997 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,247 |

*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}

**C2** population constraint: LOEUF 0.909, pLI 2.4382e-16, missense-Z 2.3109. *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 **709** lies in the peptidase s1 domain.

AlphaFold model confidence (whole protein): pLDDT 88.61, 66% of residues very-high.

**14 experimental structure(s)** (PDB): [2I6Q](https://www.rcsb.org/structure/2I6Q), [2I6S](https://www.rcsb.org/structure/2I6S), [3ERB](https://www.rcsb.org/structure/3ERB), [8ACF](https://www.rcsb.org/structure/8ACF), [8ACI](https://www.rcsb.org/structure/8ACI), [9QJ4](https://www.rcsb.org/structure/9QJ4).

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

*Describes the biological roles of C2 (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}

C2 participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Activation of C3 and C5](https://reactome.org/content/detail/R-HSA-174577) | curated |
| [Initial triggering of complement](https://reactome.org/content/detail/R-HSA-166663) | curated |
| [Regulation of Complement cascade](https://reactome.org/content/detail/R-HSA-977606) | curated |

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

**Biological process:** complement activation, complement activation, GZMK pathway, positive regulation of apoptotic cell clearance.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-12-19.

**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 | 2025-12-19 |

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

## Similar variants {#similar}

Related C2 variant pages (same residue, condition, or type): [C2 c.1902+5G>A](/variant/c2-c-1902-plus-5g-a), [C2 c.2029+5G>A](/variant/c2-c-2029-plus-5g-a), [C2 p.Ala363Thr](/variant/c2-p-ala363thr), [C2 p.Ala682Glu](/variant/c2-p-ala682glu), [C2 p.Arg124Gln](/variant/c2-p-arg124gln), [C2 p.Arg129His](/variant/c2-p-arg129his), [C2 p.Arg174Cys](/variant/c2-p-arg174cys), [C2 p.Arg176Cys](/variant/c2-p-arg176cys).

### 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 2807544). 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.*