# NM_000065.5(C6):c.1967G>C (p.Arg656Pro)

https://sugi.bio/variant/c6-p-arg656pro

## Summary

**C6 p.Arg656Pro (c.1967G>C)** is classified **Uncertain significance** in C6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-16). AlphaMissense: likely pathogenic (0.6698); Absent from gnomAD v4.1.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the C6 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, 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 | [C6](https://sugi.bio/atlas/gene/C6/) |
| Protein change (HGVS p.) | p.Arg656Pro |
| Coding change (HGVS c.) | c.1967G>C |
| MANE Select transcript | [NM_000065](https://www.ncbi.nlm.nih.gov/nuccore/NM_000065) |
| Variant type | single nucleotide variant |
| Location | chr5:41158675-41158675 (GRCh38) |
| ClinVar | [VCV4712660](https://www.ncbi.nlm.nih.gov/clinvar/variation/4712660/) |

**All HGVS expressions:** `LRG_29:g.107764G>C`, `LRG_29t1:c.1967G>C`, `NC_000005.10:g.41158675C>G`, `NC_000005.9:g.41158777C>G`, `NG_011582.1:g.107764G>C`, `NM_000065.5:c.1967G>C`, `NM_001115131.4:c.1967G>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.6698)
- REVEL 0.335 (indeterminate)
- SaProt LLR -5.915 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense calls this damaging; SaProt does not; REVEL makes no call
- Conservation: phyloP 5.987, GERP 1.73, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 27.8**. 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 1.09** across the covering region of the MANE Select transcript (41,142,828–41,203,230), spanning 60,402 bp. Chi-square p 0.0034. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>T, Δ0.80 donor loss), 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**C6** population constraint: LOEUF 1.008, pLI 6.1993e-27, missense-Z -0.34752. *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 **656** lies in the sushi 1 domain; the 'ccp 1' region; a β-strand; the 'c5b-binding domain' region.

AlphaFold model confidence (whole protein): pLDDT 79.72, 13% of residues very-high.

**11 experimental structure(s)** (PDB): [3T5O](https://www.rcsb.org/structure/3T5O), [4A5W](https://www.rcsb.org/structure/4A5W), [4E0S](https://www.rcsb.org/structure/4E0S), [6H03](https://www.rcsb.org/structure/6H03), [6H04](https://www.rcsb.org/structure/6H04), [7NYC](https://www.rcsb.org/structure/7NYC).

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

*Describes the biological roles of C6 (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}

C6 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:** complement activation, killing of cells of another organism, complement activation, GZMK pathway.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-02-16.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-02-16 |

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

## Similar variants {#similar}

Related C6 variant pages (same residue, condition, or type): [C6 p.Arg656Gln](/variant/c6-p-arg656gln), [C6 p.Arg656Trp](/variant/c6-p-arg656trp), [C6 p.Arg596Ter](/variant/c6-p-arg596ter), [C6 p.Arg606Ter](/variant/c6-p-arg606ter), [C6 p.Cys218Ter](/variant/c6-p-cys218ter), [C6 p.Tyr683Ter](/variant/c6-p-tyr683ter), [C6 p.Ala21Val](/variant/c6-p-ala21val), [C6 p.Ala396Gly](/variant/c6-p-ala396gly).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 4712660). 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.*