# NM_198239.2(CCN6):c.589G>C (p.Ala197Pro)

https://sugi.bio/variant/ccn6-p-ala197pro

## Summary

**CCN6 p.Ala197Pro (c.589G>C)** is classified **Pathogenic/Likely pathogenic** in CCN6 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-21). AlphaMissense: likely benign (0.1567); Very rare (popmax 0.000593%, nfe); Associated with progressive pseudorheumatoid arthropathy of childhood.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs1554313639 · 4 submitters · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.000593%, nfe)

## For patients & families {#patients}

This is a change in the CCN6 gene that is considered likely disease-causing, submitted by 4 submitters, and is linked to progressive pseudorheumatoid arthropathy of childhood.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Childhood |
| Prevalence | 1-9 / 1 000 000 (Europe) |
| Clinical trials | 2 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | CCN6 is a diagnostic-grade gene on 2 Genomics England panels |

**Commonly reported features of Progressive pseudorheumatoid dysplasia** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Platyspondyly — Very frequent (99-80%)
- Joint swelling — Very frequent (99-80%)
- Waddling gait — Very frequent (99-80%)
- Spondyloepiphyseal dysplasia — Very frequent (99-80%)
- Irregular vertebral endplates — Very frequent (99-80%)
- Narrow small joints of the hand — Very frequent (99-80%)
- Polyarticular arthropathy — Very frequent (99-80%)
- Wrist swelling — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0009184/index) · [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.Ala197Pro |
| Coding change (HGVS c.) | c.589G>C |
| MANE Select transcript | [NM_198239](https://www.ncbi.nlm.nih.gov/nuccore/NM_198239) |
| dbSNP | [rs1554313639](https://www.ncbi.nlm.nih.gov/snp/rs1554313639/) |
| Variant type | single nucleotide variant |
| Location | chr6:112064997-112064997 (GRCh38) |
| ClinVar | [VCV637051](https://www.ncbi.nlm.nih.gov/clinvar/variation/637051/) |

**All HGVS expressions:** `NC_000006.11:g.112386200G>C`, `NC_000006.12:g.112064997G>C`, `NG_011748.1:g.15923G>C`, `NM_003880.4:c.589G>C`, `NM_198239.2:c.589G>C`, `NR_125353.2:n.843G>C`, `NR_125354.3:n.670G>C`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — AlphaMissense predicts likely-benign.

- AlphaMissense **likely benign** (0.1567) — ⚠ discordant with the pathogenic call
- REVEL 0.607 (indeterminate)
- SaProt LLR -6.305 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- SpliceAI predicts **donor loss** (Δ 0.43) — consistent with the pathogenic call
- Conservation: phyloP 8.518, GERP 2.46, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 33.0**. 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 0.89** across the covering region of the MANE Select transcript (112,054,358–112,069,617), spanning 15,259 bp. Chi-square p 0.028. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.43**, acceptor gain **0.00**, donor gain **0.04**. Largest is donor loss.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.43**, acceptor gain **0.00**, donor gain **0.04**.
- Pangolin: Δ**0.22** (loss), gain 0.02 / 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 **0.000593%** (nfe) · FAF95 0.000247% · FAF99 0.000159% · 7/1,179,910 in the highest group · 7/1,613,844 alleles overall — very rare (popmax 0.000593%, 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 **197** 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/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-21.

**Submitter consensus:** conflicting (3 Pathogenic, 1 Likely pathogenic).

**Submission history:** 4 submissions (2018–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Likely pathogenic | criteria provided, single submitter | clinical testing | 2018-07-31 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2022-05-26 |
| Clinical Genetics Laboratory, Skane University Hospital Lund | Pathogenic | criteria provided, single submitter | clinical testing | 2026-01-21 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2023-10-15 |

## Associated conditions {#conditions}

[progressive pseudorheumatoid arthropathy of childhood](https://sugi.bio/atlas/disease/progressive-pseudorheumatoid-arthropathy-of-childhood/).

**Reported phenotype names (ClinVar):** Progressive pseudorheumatoid dysplasia, not provided, none provided, SPONDYLOEPIPHYSEAL DYSPLASIA TARDA WITH PROGRESSIVE ARTHROPATHY, Progressive Pseudorheumatoid Arthropathy of Childhood.

## Similar variants {#similar}

Related CCN6 variant pages (same residue, condition, or type): [CCN6 c.49-1G>A](/variant/ccn6-c-49-minus-1g-a), [CCN6 c.590-1G>C](/variant/ccn6-c-590-minus-1g-c), [CCN6 p.Cys223Gly](/variant/ccn6-p-cys223gly), [CCN6 p.Cys337Tyr](/variant/ccn6-p-cys337tyr), [CCN6 p.Cys52Ter](/variant/ccn6-p-cys52ter), [CCN6 p.Cys78Tyr](/variant/ccn6-p-cys78tyr), [CCN6 p.Met1Val](/variant/ccn6-p-met1val), [CCN6 p.Ser39Ter](/variant/ccn6-p-ser39ter).

### 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 637051). 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.*