# NM_000063.6(C2):c.728G>A (p.Arg243His)

https://sugi.bio/variant/c2-p-arg243his

## Summary

**C2 p.Arg243His (c.728G>A)** is classified **Uncertain significance** in C2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-04). AlphaMissense: likely benign (0.3164); Very rare (popmax 0.000932%, nfe).

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs201130773 · 2 submitters · AlphaMissense likely benign · very rare (popmax 0.000932%, nfe)

## For patients & families {#patients}

This is a change in the C2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters.

*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.Arg243His |
| Coding change (HGVS c.) | c.728G>A |
| MANE Select transcript | [NM_000063](https://www.ncbi.nlm.nih.gov/nuccore/NM_000063) |
| dbSNP | [rs201130773](https://www.ncbi.nlm.nih.gov/snp/rs201130773/) |
| Variant type | single nucleotide variant |
| Location | chr6:31934178-31934178 (GRCh38) |
| ClinVar | [VCV1375438](https://www.ncbi.nlm.nih.gov/clinvar/variation/1375438/) |

**All HGVS expressions:** `LRG_26:g.11690G>A`, `LRG_26t1:c.728G>A`, `NC_000006.11:g.31901955G>A`, `NC_000006.12:g.31934178G>A`, `NG_011730.1:g.11690G>A`, `NM_000063.4:c.728G>A`, `NM_000063.6:c.728G>A`, `NM_001145903.3:c.332G>A`, `NM_001178063.3:c.346+213G>A`, `NM_001282457.2:c.111+395G>A`, `NM_001282458.2:c.641G>A`, `NM_001282459.2:c.728G>A`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.3164)
- REVEL 0.471 (indeterminate)
- SaProt LLR -5.578 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- SpliceAI predicts **acceptor loss** (Δ 0.21) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 11.826, GERP 1.74, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 32.0**. 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 0.84** across the covering region of the MANE Select transcript (31,927,753–31,945,354), spanning 17,601 bp. Chi-square p 1.1e-06. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.21**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**. Largest is acceptor loss, 12 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Pangolin: Δ**0.22** (loss), gain 0.01 / loss 0.22. 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 **0.000932%** (nfe) · FAF95 0.0005% · FAF99 0.000366% · 11/1,180,024 in the highest group · 11/1,614,206 alleles overall — very rare (popmax 0.000932%, 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}

**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 **243** lies in a functional site (cleavage; by c1s, masp2 and gzmk).

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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-09-04.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2022–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-09-04 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-07-19 |

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

## Similar variants {#similar}

Related C2 variant pages (same residue, condition, or type): [C2 p.Arg243Cys](/variant/c2-p-arg243cys), [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).

### 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 1375438). 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.*