# NM_024877.4(CCNP):c.11G>C (p.Arg4Thr)

https://sugi.bio/variant/ccnp-p-arg4thr

## Summary

**CCNP p.Arg4Thr (c.11G>C)** is classified **Uncertain significance** in CCNP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-14). AlphaMissense: likely benign (0.164); Very rare (popmax 0.00461%, eas).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.00461%, eas)

## For patients & families {#patients}

This is a change in the CCNP 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 | [CCNP](https://sugi.bio/atlas/gene/CCNP/) |
| Protein change (HGVS p.) | p.Arg4Thr |
| Coding change (HGVS c.) | c.11G>C |
| MANE Select transcript | [NM_024877](https://www.ncbi.nlm.nih.gov/nuccore/NM_024877) |
| Variant type | single nucleotide variant |
| Location | chr19:40226631-40226631 (GRCh38) |
| ClinVar | [VCV4222194](https://www.ncbi.nlm.nih.gov/clinvar/variation/4222194/) |

**All HGVS expressions:** `NC_000019.10:g.40226631C>G`, `NC_000019.9:g.40732538C>G`, `NG_141394.1:g.209C>G`, `NM_001411133.1:c.11G>C`, `NM_024877.4:c.11G>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.164)
- REVEL 0.039 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -7.184 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **donor loss** (Δ 0.22) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 4.867, GERP 1.61, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 23.4**. 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 1.04** across the covering region of the MANE Select transcript (40,223,055–40,226,641), spanning 3,586 bp. Chi-square p 0.45. 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 **0.22**, acceptor gain **0.00**, donor gain **0.01**. Largest is donor loss.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.22**, acceptor gain **0.00**, donor gain **0.01**.
- Population frequency (gnomAD v4.1): grpmax **0.00461%** (eas) · FAF95 0.000764% · FAF99 0.000286% · 2/43,400 in the highest group · 2/1,428,146 alleles overall — very rare (popmax 0.00461%, eas).

*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}

**CCNP** population constraint: LOEUF 1.397, pLI 1.1726e-06, missense-Z -0.43687. *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 **4** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 70.87, 38% of residues very-high.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-08-14.

**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 | 2025-08-14 |

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

## Similar variants {#similar}

Related CCNP variant pages (same residue, condition, or type): [CCNP p.Ala173Ser](/variant/ccnp-p-ala173ser), [CCNP p.Ala186Val](/variant/ccnp-p-ala186val), [CCNP p.Ala243Val](/variant/ccnp-p-ala243val), [CCNP p.Ala265Thr](/variant/ccnp-p-ala265thr), [CCNP p.Ala37Ser](/variant/ccnp-p-ala37ser), [CCNP p.Ala68Glu](/variant/ccnp-p-ala68glu), [CCNP p.Ala81Ser](/variant/ccnp-p-ala81ser), [CCNP p.Arg101His](/variant/ccnp-p-arg101his).

### 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 4222194). 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.*