# NM_198320.5(CPM):c.865C>T (p.Arg289Cys)

https://sugi.bio/variant/cpm-p-arg289cys

## Summary

**CPM p.Arg289Cys (c.865C>T)** is classified **Uncertain significance** in CPM (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-17). AlphaMissense: likely benign (0.2451); Ultra-rare (popmax 0.0201%, eas).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs538250941 · 1 submitter · AlphaMissense likely benign · ultra-rare (popmax 0.0201%, eas)

## For patients & families {#patients}

This is a change in the CPM 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 | [CPM](https://sugi.bio/atlas/gene/CPM/) |
| Protein change (HGVS p.) | p.Arg289Cys |
| Coding change (HGVS c.) | c.865C>T |
| MANE Select transcript | [NM_198320](https://www.ncbi.nlm.nih.gov/nuccore/NM_198320) |
| dbSNP | [rs538250941](https://www.ncbi.nlm.nih.gov/snp/rs538250941/) |
| Variant type | single nucleotide variant |
| Location | chr12:68866971-68866971 (GRCh38) |
| ClinVar | [VCV2569725](https://www.ncbi.nlm.nih.gov/clinvar/variation/2569725/) |

**All HGVS expressions:** `NC_000012.11:g.69260751G>A`, `NC_000012.12:g.68866971G>A`, `NM_001005502.3:c.865C>T`, `NM_001413387.1:c.901C>T`, `NM_001413388.1:c.865C>T`, `NM_001413389.1:c.865C>T`, `NM_001413390.1:c.865C>T`, `NM_001413391.1:c.865C>T`, `NM_001413392.1:c.742C>T`, `NM_001413393.1:c.787+2354C>T`, `NM_001413394.1:c.787+2354C>T`, `NM_001413395.1:c.622C>T`, `NM_001413396.1:c.622C>T`, `NM_001413397.1:c.502C>T`, `NM_001413398.1:c.502C>T`, `NM_001413399.1:c.502C>T`, `NM_001413400.1:c.502C>T`, `NM_001413401.1:c.502C>T`, `NM_001413402.1:c.865C>T`, `NM_001413403.1:c.298C>T`, `NM_001413404.1:c.298C>T`, `NM_001874.5:c.865C>T`, `NM_198320.5:c.865C>T`, `NR_182142.1:n.908C>T`, `NR_182143.1:n.1629C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.2451)
- REVEL 0.054 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -7.726 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 5.852, GERP 0.932, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 27.8**. 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 0.80** across the covering region of the MANE Select transcript (68,856,440–68,932,837), spanning 76,397 bp. Chi-square p 2.5e-06. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>C, Δ0.47 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0201%** (eas) · FAF95 0.0104% · FAF99 0.00779% · 9/44,870 in the highest group · 21/1,614,006 alleles overall — ultra-rare (popmax 0.0201%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.0201% | 4,986 |
| Admixed American | 0.00333% | 30,008 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,253 |
| African / African-American | 0.00133% | 75,026 |
| European (non-Finnish) | 0.000593% | 168,559 |

*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}

**CPM** population constraint: LOEUF 1.017, pLI 1.1796e-08, missense-Z 2.1417. *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 **289** lies in the peptidase m14 domain.

AlphaFold model confidence (whole protein): pLDDT 90.49, 82% of residues very-high.

**1 experimental structure(s)** (PDB): [1UWY](https://www.rcsb.org/structure/1UWY).

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

*Describes the biological roles of CPM (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}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Post-translational modification: synthesis of GPI-anchored proteins](https://reactome.org/content/detail/R-HSA-163125) | curated |

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-03-17.

**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 | 2023-03-17 |

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

## Similar variants {#similar}

Related CPM variant pages (same residue, condition, or type): [CPM p.Arg289Gly](/variant/cpm-p-arg289gly), [CPM p.Arg289His](/variant/cpm-p-arg289his), [CPM p.Ala209Ser](/variant/cpm-p-ala209ser), [CPM p.Ala36Thr](/variant/cpm-p-ala36thr), [CPM p.Arg118Gln](/variant/cpm-p-arg118gln), [CPM p.Arg213Gln](/variant/cpm-p-arg213gln), [CPM p.Asn299Ser](/variant/cpm-p-asn299ser), [CPM p.Asn300Lys](/variant/cpm-p-asn300lys).

### 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 2569725). 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.*