# NM_198239.2(CCN6):c.587del (p.Pro196fs)

https://sugi.bio/variant/ccn6-p-pro196fs

## Summary

**CCN6 p.Pro196fs (c.587del)** is classified **Pathogenic** in CCN6 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-12). Very rare (popmax 0.00102%, nfe).

**At a glance:** Pathogenic · review: Single submitter · rsID rs782293823 · 1 submitter · very rare (popmax 0.00102%, nfe)

## For patients & families {#patients}

This is a change in the CCN6 gene that is reported as disease-causing, but on limited review, 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 | [CCN6](https://sugi.bio/atlas/gene/CCN6/) |
| Protein change (HGVS p.) | p.Pro196fs |
| Coding change (HGVS c.) | c.587del |
| MANE Select transcript | [NM_198239](https://www.ncbi.nlm.nih.gov/nuccore/NM_198239) |
| dbSNP | [rs782293823](https://www.ncbi.nlm.nih.gov/snp/rs782293823/) |
| Variant type | Deletion |
| Location | chr6:112064994-112064994 (GRCh38) |
| ClinVar | [VCV1680467](https://www.ncbi.nlm.nih.gov/clinvar/variation/1680467/) |

**All HGVS expressions:** `NC_000006.11:g.112386198del`, `NC_000006.12:g.112064995del`, `NG_011748.1:g.15921del`, `NM_003880.4:c.587del`, `NM_198239.2:c.587del`, `NR_125353.2:n.841del`, `NR_125354.3:n.668del`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 7.367, GERP 2.46, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.055, pLI 5.3805e-09. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 3 of 5**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00102%** (nfe) · FAF95 0.000542% · FAF99 0.000428% · 12/1,179,902 in the highest group · 12/1,461,654 alleles overall — very rare (popmax 0.00102%, 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}

**CCN6** population constraint: LOEUF 1.055, pLI 5.3805e-09, missense-Z 1.1806; ClinGen dosage — haploinsufficiency 30, triplosensitivity Not yet evaluated (0–3 scale). *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):

- **progressive pseudorheumatoid arthropathy of childhood** — Definitive (AR)

## Protein context {#protein}

Residue **196** lies in a UniProt-annotated variant site (in pprd).

AlphaFold model confidence (whole protein): pLDDT 74.30, 24% of residues very-high.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-07-12.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2023-07-12 |

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

## Similar variants {#similar}

Related CCN6 variant pages (same residue, condition, or type): [CCN6 p.Asn178_Cys179insTer](/variant/ccn6-p-asn178-cys179inster), [CCN6 p.Glu84fs](/variant/ccn6-p-glu84fs), [CCN6 p.Ser236fs](/variant/ccn6-p-ser236fs), [CCN6 c.783+1_783+6del](/variant/ccn6-c-783-plus-1-783-plus-6del), [CCN6 p.Ala15fs](/variant/ccn6-p-ala15fs), [CCN6 p.Glu32fs](/variant/ccn6-p-glu32fs), [CCN6 p.Gly171fs](/variant/ccn6-p-gly171fs), [CCN6 p.Leu210fs](/variant/ccn6-p-leu210fs).

### 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 1680467). 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.*