# NM_001901.4(CCN2):c.754A>G (p.Lys252Glu)

https://sugi.bio/variant/ccn2-p-lys252glu

## Summary

**CCN2 p.Lys252Glu (c.754A>G)** is classified **Uncertain significance** in CCN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-26). AlphaMissense: likely benign (0.2905); Very rare (popmax 0.00386%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.00386%, nfe)

## For patients & families {#patients}

This is a change in the CCN2 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 | [CCN2](https://sugi.bio/atlas/gene/CCN2/) |
| Protein change (HGVS p.) | p.Lys252Glu |
| Coding change (HGVS c.) | c.754A>G |
| MANE Select transcript | [NM_001901](https://www.ncbi.nlm.nih.gov/nuccore/NM_001901) |
| Variant type | single nucleotide variant |
| Location | chr6:131949560-131949560 (GRCh38) |
| ClinVar | [VCV4221983](https://www.ncbi.nlm.nih.gov/clinvar/variation/4221983/) |

**All HGVS expressions:** `NC_000006.11:g.132270700T>C`, `NC_000006.12:g.131949560T>C`, `NG_016131.1:g.6819A>G`, `NG_016131.2:g.6812A>G`, `NM_001901.4:c.754A>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.2905)
- REVEL 0.512 (indeterminate)
- SaProt LLR -10.147 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** SaProt calls this damaging; AlphaMissense does not; REVEL makes no call
- SpliceAI predicts **acceptor loss** (Δ 0.70) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 6.179, GERP 1.67, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 28.7**. 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 0.94** across the covering region of the MANE Select transcript (131,949,267–131,951,172), spanning 1,905 bp. Chi-square p 0.18. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.70**, donor loss **0.00**, acceptor gain **0.01**, donor gain **0.00**. Largest is acceptor loss, 3 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.*
- Population frequency (gnomAD v4.1): grpmax **0.00386%** (nfe) · FAF95 0.00294% · FAF99 0.00262% · 45/1,166,626 in the highest group · 45/1,443,398 alleles overall — very rare (popmax 0.00386%, 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}

**CCN2** population constraint: LOEUF 1.05, pLI 2.6895e-06, missense-Z -0.22824. *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 **252** lies in the 'heparin-binding' region.

AlphaFold model confidence (whole protein): pLDDT 78.43, 32% of residues very-high.

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

*Describes the biological roles of CCN2 (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}

CCN2 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [RUNX3 regulates YAP1-mediated transcription](https://reactome.org/content/detail/R-HSA-8951671) | curated |
| [YAP1- and WWTR1 (TAZ)-stimulated gene expression](https://reactome.org/content/detail/R-HSA-2032785) | curated |

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

**Biological process:** osteoblast differentiation, positive regulation of cell differentiation, positive regulation of JNK cascade, positive regulation of stress fiber assembly, positive regulation of ERK1 and ERK2 cascade.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-06-26.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-06-26 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related CCN2 variant pages (same residue, condition, or type): [CCN2 c.290-6C>T](/variant/ccn2-c-290-minus-6c-t), [CCN2 c.67-4G>A](/variant/ccn2-c-67-minus-4g-a), [CCN2 p.Ala101Ser](/variant/ccn2-p-ala101ser), [CCN2 p.Ala208Thr](/variant/ccn2-p-ala208thr), [CCN2 p.Ala45Val](/variant/ccn2-p-ala45val), [CCN2 p.Ala61Thr](/variant/ccn2-p-ala61thr), [CCN2 p.Arg34Gly](/variant/ccn2-p-arg34gly), [CCN2 p.Arg42Gly](/variant/ccn2-p-arg42gly).

### 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 4221983). 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.*