# NM_003859.3(DPM1):c.397A>C (p.Arg133=)

https://sugi.bio/variant/dpm1-p-arg133

## Summary

**DPM1 p.Arg133= (c.397A>C)** is classified **Uncertain significance** in DPM1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-05). Absent from gnomAD v4.1; Associated with congenital disorder of glycosylation type 1E.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2515723325 · 1 submitter · 1 linked condition · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the DPM1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to congenital disorder of glycosylation type 1E.

*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) | Infancy, Neonatal |
| Diagnostic panels | DPM1 is a diagnostic-grade gene on 13 Genomics England panels |

**Commonly reported features of DPM1-CDG** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Seizure — Very frequent (99-80%)
- Elevated circulating creatine kinase concentration — Very frequent (99-80%)
- Secondary microcephaly — Very frequent (99-80%)
- Floppy infant — Very frequent (99-80%)
- Neurodevelopmental delay — Very frequent (99-80%)
- Hypertelorism — Frequent (79-30%)
- Failure to thrive — Frequent (79-30%)
- Reduced antithrombin III activity — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0009831/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DPM1](https://sugi.bio/atlas/gene/DPM1/) |
| Protein change (HGVS p.) | p.Arg133= |
| Coding change (HGVS c.) | c.397A>C |
| MANE Select transcript | [NM_003859](https://www.ncbi.nlm.nih.gov/nuccore/NM_003859) |
| dbSNP | [rs2515723325](https://www.ncbi.nlm.nih.gov/snp/rs2515723325/) |
| Variant type | single nucleotide variant |
| Location | chr20:50945738-50945738 (GRCh38) |
| ClinVar | [VCV2002305](https://www.ncbi.nlm.nih.gov/clinvar/variation/2002305/) |

**All HGVS expressions:** `NC_000020.10:g.49562275T>G`, `NC_000020.11:g.50945738T>G`, `NG_008923.1:g.17786A>C`, `NM_001317034.1:c.397A>C`, `NM_001317035.1:c.397A>C`, `NM_001317036.1:c.397A>C`, `NM_003859.3:c.397A>C`, `NR_133648.2:n.406A>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 (below), not from a missing predictor score.
- Conservation: phyloP 6.201, GERP 1.76, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 18.07**. 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.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (T>A, Δ0.28 donor loss), 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**DPM1** population constraint: LOEUF 1.005, pLI 1.934e-05, missense-Z 0.33652; ClinGen dosage — haploinsufficiency 30, triplosensitivity 0 (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):

- **congenital disorder of glycosylation type 1E** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 88.61, 65% of residues very-high.

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

*Describes the biological roles of DPM1 (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:** DPM1's established molecular role includes dolichyl-phosphate beta-D-mannosyltransferase activity. In Reactome, DPM1 is annotated in disease pathway(s) including **Defective DPM1 causes DPM1-CDG**, **Defective DPM2 causes DPM2-CDG**.

**Disease mechanism (Reactome):** DPM1 loss or alteration is curated in [Defective DPM1 causes DPM1-CDG](https://reactome.org/content/detail/R-HSA-4717374), [Defective DPM2 causes DPM2-CDG](https://reactome.org/content/detail/R-HSA-4719377), [Defective DPM3 causes DPM3-CDG](https://reactome.org/content/detail/R-HSA-4719360).

### Pathways affected {#pathways}

DPM1 participates in **5 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective DPM1 causes DPM1-CDG](https://reactome.org/content/detail/R-HSA-4717374) | curated |
| ⚕ [Defective DPM2 causes DPM2-CDG](https://reactome.org/content/detail/R-HSA-4719377) | curated |
| ⚕ [Defective DPM3 causes DPM3-CDG](https://reactome.org/content/detail/R-HSA-4719360) | curated |
| ⚕ [Maturation of DENV proteins](https://reactome.org/content/detail/R-HSA-9918432) | curated |
| [Synthesis of dolichyl-phosphate mannose](https://reactome.org/content/detail/R-HSA-162699) | curated |

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

**Molecular function:** dolichyl-phosphate beta-D-mannosyltransferase activity.

**Biological process:** GPI anchor biosynthetic process, protein O-linked glycosylation via mannose, dolichyl monophosphate biosynthetic process, dolichol phosphate mannose biosynthetic process.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-08-05.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-08-05 |

## Associated conditions {#conditions}

[congenital disorder of glycosylation type 1E](https://sugi.bio/atlas/disease/congenital-disorder-of-glycosylation-type-1e/).

**Reported phenotype names (ClinVar):** Congenital disorder of glycosylation type 1E, CDG Ie, CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ie.

## Similar variants {#similar}

Related DPM1 variant pages (same residue, condition, or type): [DPM1 p.Arg92Gly](/variant/dpm1-p-arg92gly), [DPM1 p.His124Arg](/variant/dpm1-p-his124arg), [DPM1 p.Met1Leu](/variant/dpm1-p-met1leu), [DPM1 c.*12T>C](/variant/dpm1-c-star-12t-c), [DPM1 p.Ala109Val](/variant/dpm1-p-ala109val), [DPM1 p.Arg12Met](/variant/dpm1-p-arg12met), [DPM1 p.Arg191Gln](/variant/dpm1-p-arg191gln), [DPM1 p.Arg20Leu](/variant/dpm1-p-arg20leu).

### 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 2002305). 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.*