# NM_153741.2(DPM3):c.124C>G (p.Pro42Ala)

https://sugi.bio/variant/dpm3-p-pro42ala

## Summary

**DPM3 p.Pro42Ala (c.124C>G)** is classified **Pathogenic/Likely pathogenic** in DPM3 (ClinVar, No assertion criteria, 2 submitters; last evaluated 2020-08-25). AlphaMissense: ambiguous (0.4311); Absent from gnomAD v4.1; Associated with DPM3-congenital disorder of glycosylation.

**At a glance:** Pathogenic/Likely pathogenic · review: No assertion criteria · rsID rs745692004 · 2 submitters · 2 linked conditions · AlphaMissense ambiguous · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the DPM3 gene that is considered likely disease-causing, submitted by 2 submitters, and is linked to DPM3-congenital disorder of glycosylation.

*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) | Childhood |
| Diagnostic panels | DPM3 is a diagnostic-grade gene on 8 Genomics England panels |

**Commonly reported features of DPM3-CDG** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Decreased sialylation of O-linked protein glycosylation — Very frequent (99-80%)
- Reduced tendon reflexes — Frequent (79-30%)
- Muscle weakness — Frequent (79-30%)
- Dilated cardiomyopathy — Frequent (79-30%)
- Pes planus — Frequent (79-30%)
- Intellectual disability, profound — Frequent (79-30%)
- Stroke-like episode — Frequent (79-30%)
- Elevated circulating hepatic transaminase concentration — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0012395/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DPM3](https://sugi.bio/atlas/gene/DPM3/) |
| Protein change (HGVS p.) | p.Pro42Ala |
| Coding change (HGVS c.) | c.124C>G |
| MANE Select transcript | [NM_153741](https://www.ncbi.nlm.nih.gov/nuccore/NM_153741) |
| dbSNP | [rs745692004](https://www.ncbi.nlm.nih.gov/snp/rs745692004/) |
| Variant type | single nucleotide variant |
| Location | chr1:155140117-155140117 (GRCh38) |
| ClinVar | [VCV694292](https://www.ncbi.nlm.nih.gov/clinvar/variation/694292/) |

**All HGVS expressions:** `NC_000001.10:g.155112593G>C`, `NC_000001.11:g.155140117G>C`, `NG_012871.1:g.5404C>G`, `NM_018973.4:c.214C>G`, `NM_153741.2:c.124C>G`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense makes no call; REVEL and SaProt both call this damaging; AlphaMissense makes no call — descriptive only.

- AlphaMissense **ambiguous** (0.4311) — no call either way
- REVEL 0.931 (moderately pathogenic-leaning)
- SaProt LLR -12.342 (damaging)
- → **In-silico consensus:** REVEL and SaProt both call this damaging; AlphaMissense makes no call
- Conservation: phyloP 11.695, GERP 1.86, phastCons 1 — highly conserved
- CADD: **PHRED 28.2**. 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 0.93** across the covering region of the MANE Select transcript (155,139,965–155,140,240), spanning 275 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: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- 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}

**DPM3** population constraint: LOEUF 1.364, pLI 0.0094613, missense-Z 0.50157; 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):

- **DPM3-congenital disorder of glycosylation** — Moderate (AR)

## Protein context {#protein}

Residue **42** lies in a UniProt-annotated variant site (in mddgb15; uncertain significance).

AlphaFold model confidence (whole protein): pLDDT 88.73, 64% of residues very-high.

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

*Describes the biological roles of DPM3 (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:** DPM3's established molecular role includes enzyme activator activity. In Reactome, DPM3 is annotated in disease pathway(s) including **Defective DPM1 causes DPM1-CDG**, **Defective DPM2 causes DPM2-CDG**.

**Disease mechanism (Reactome):** DPM3 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}

DPM3 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:** enzyme activator activity.

**Biological process:** dolichyl monophosphate biosynthetic process, dolichol phosphate mannose biosynthetic process.

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2020-08-25.

**Submitter consensus:** conflicting (1 Pathogenic, 1 Likely pathogenic).

**Submission history:** 2 submissions (2019–2020); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2020-08-25 |
| Neurology Department, Peking University First Hospital | Likely pathogenic | no assertion criteria provided | clinical testing | 2019-06-23 |

## Associated conditions {#conditions}

[DPM3-congenital disorder of glycosylation](https://sugi.bio/atlas/disease/dpm3-congenital-disorder-of-glycosylation/), [muscular dystrophy-dystroglycanopathy (congenital with impaired intellectual development), type B, 15](https://sugi.bio/atlas/disease/muscular-dystrophy-dystroglycanopathy-congenital-with-impaired-intellectual-development-type-b-15/).

**Reported phenotype names (ClinVar):** DPM3-congenital disorder of glycosylation, Muscular dystrophy-dystroglycanopathy (congenital with impaired intellectual development), type B, 15, DPM3-CDG, MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (LIMB-GIRDLE), TYPE C, 15, CDG Io, CDG1(DPM3), MUSCULAR DYSTROPHY, CONGENITAL, DPM3-RELATED.

## Similar variants {#similar}

Related DPM3 variant pages (same residue, condition, or type): [DPM3 p.Ala70Thr](/variant/dpm3-p-ala70thr), [DPM3 p.Ala86Asp](/variant/dpm3-p-ala86asp), [DPM3 p.Arg60Cys](/variant/dpm3-p-arg60cys), [DPM3 p.Arg60Leu](/variant/dpm3-p-arg60leu), [DPM3 p.Glu73Ala](/variant/dpm3-p-glu73ala), [DPM3 p.Gly89Glu](/variant/dpm3-p-gly89glu), [DPM3 p.Trp7Arg](/variant/dpm3-p-trp7arg), [DPM3 p.Tyr59Ser](/variant/dpm3-p-tyr59ser).

### 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 694292). 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.*