# NM_003859.3(DPM1):c.385C>T (p.Pro129Ser)

https://sugi.bio/variant/dpm1-p-pro129ser

## Summary

**DPM1 p.Pro129Ser (c.385C>T)** is classified **Uncertain significance** in DPM1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-02). AlphaMissense: likely benign (0.255); Very rare (popmax 0.00304%, nfe); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs752831768 · 2 submitters · 2 linked conditions · AlphaMissense likely benign · very rare (popmax 0.00304%, nfe)

## 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 2 submitters, and is linked to Inborn genetic diseases.

*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 | [DPM1](https://sugi.bio/atlas/gene/DPM1/) |
| Protein change (HGVS p.) | p.Pro129Ser |
| Coding change (HGVS c.) | c.385C>T |
| MANE Select transcript | [NM_003859](https://www.ncbi.nlm.nih.gov/nuccore/NM_003859) |
| dbSNP | [rs752831768](https://www.ncbi.nlm.nih.gov/snp/rs752831768/) |
| Variant type | single nucleotide variant |
| Location | chr20:50945750-50945750 (GRCh38) |
| ClinVar | [VCV650177](https://www.ncbi.nlm.nih.gov/clinvar/variation/650177/) |

**All HGVS expressions:** `NC_000020.10:g.49562287G>A`, `NC_000020.11:g.50945750G>A`, `NG_008923.1:g.17774C>T`, `NM_001317034.1:c.385C>T`, `NM_001317035.1:c.385C>T`, `NM_001317036.1:c.385C>T`, `NM_003859.3:c.385C>T`, `NR_133648.2:n.394C>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** (0.255)
- REVEL 0.507 (indeterminate)
- SaProt LLR -8.924 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- SpliceAI predicts **donor loss** (Δ 0.38) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 11.877, GERP 1.76, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 26.7**. 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 1.09** across the covering region of the MANE Select transcript (50,942,068–50,958,523), spanning 16,455 bp. Chi-square p 0.19. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.28**, donor loss **0.38**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss.
- SpliceAI deltas (masked): acceptor loss **0.28**, donor loss **0.38**, acceptor gain **0.00**, donor gain **0.00**.
- Pangolin: Δ**0.31** (loss), gain 0.00 / loss 0.31. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00304%** (nfe) · FAF95 0.00221% · FAF99 0.00195% · 35/1,152,152 in the highest group · 35/1,581,966 alleles overall — very rare (popmax 0.00304%, 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}

**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 Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-09-02.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2022–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-04-13 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-09-02 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Inborn genetic diseases, 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.Pro129Thr](/variant/dpm1-p-pro129thr), [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).

### 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 650177). 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.*