# NM_016308.3(CMPK1):c.439T>C (p.Ser147Pro)

https://sugi.bio/variant/cmpk1-p-ser147pro

## Summary

**CMPK1 p.Ser147Pro (c.439T>C)** is classified **Uncertain significance** in CMPK1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-09). Ultra-rare (popmax 0.0118%, amr).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1243728313 · 1 submitter · ultra-rare (popmax 0.0118%, amr)

## For patients & families {#patients}

This is a change in the CMPK1 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 | [CMPK1](https://sugi.bio/atlas/gene/CMPK1/) |
| Protein change (HGVS p.) | p.Ser147Pro |
| Coding change (HGVS c.) | c.439T>C |
| MANE Select transcript | [NM_016308](https://www.ncbi.nlm.nih.gov/nuccore/NM_016308) |
| dbSNP | [rs1243728313](https://www.ncbi.nlm.nih.gov/snp/rs1243728313/) |
| Variant type | single nucleotide variant |
| Location | chr1:47373075-47373075 (GRCh38) |
| ClinVar | [VCV2357608](https://www.ncbi.nlm.nih.gov/clinvar/variation/2357608/) |

**All HGVS expressions:** `NC_000001.10:g.47838747T>C`, `NC_000001.11:g.47373075T>C`, `NM_001136140.2:c.292T>C`, `NM_001366135.1:c.343T>C`, `NM_016308.3:c.439T>C`, `NR_046394.2:n.595T>C`

## Computational & population evidence {#evidence}

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

- **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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor loss** (Δ 0.35) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 1.484, GERP -0.535, phastCons 1 — weakly conserved position
- CADD: **PHRED 18.44**. 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 0.59** across the covering region of the MANE Select transcript (47,334,047–47,376,742), spanning 42,695 bp. Chi-square p 4.9e-10. 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 **0.35**, acceptor gain **0.00**, donor gain **0.03**. Largest is donor loss, 4 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 **0.0118%** (amr) · FAF95 0.00547% · FAF99 0.00383% · 7/59,556 in the highest group · 7/1,609,014 alleles overall — ultra-rare (popmax 0.0118%, amr).

*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}

**CMPK1** population constraint: LOEUF 0.902, pLI 0.17633, missense-Z 0.92578. *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 **147** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 97.06, 98% of residues very-high.

**2 experimental structure(s)** (PDB): [1TEV](https://www.rcsb.org/structure/1TEV), [7E9V](https://www.rcsb.org/structure/7E9V).

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

*Describes the biological roles of CMPK1 (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.*

**How this variant is thought to act:** CMPK1's established molecular role includes nucleoside diphosphate kinase activity.


### Pathways affected {#pathways}

CMPK1 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Interconversion of nucleotide di- and triphosphates](https://reactome.org/content/detail/R-HSA-499943) | curated |

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

**Molecular function:** nucleoside diphosphate kinase activity, UMP kinase activity, nucleoside monophosphate kinase activity.

**Biological process:** UDP biosynthetic process.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-07-09.

**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 | 2021-07-09 |

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

## Similar variants {#similar}

Related CMPK1 variant pages (same residue, condition, or type): [CMPK1 p.Arg54Leu](/variant/cmpk1-p-arg54leu), [CMPK1 p.Arg6Leu](/variant/cmpk1-p-arg6leu), [CMPK1 p.Asn156Ser](/variant/cmpk1-p-asn156ser), [CMPK1 p.Glu178Lys](/variant/cmpk1-p-glu178lys), [CMPK1 p.Gly43Cys](/variant/cmpk1-p-gly43cys), [CMPK1 p.Ile207Val](/variant/cmpk1-p-ile207val), [CMPK1 p.Leu10Phe](/variant/cmpk1-p-leu10phe), [CMPK1 p.Pro24Thr](/variant/cmpk1-p-pro24thr).

### 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 2357608). 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.*