# NM_003863.4(DPM2):c.100A>G (p.Ile34Val)

https://sugi.bio/variant/dpm2-p-ile34val

## Summary

**DPM2 p.Ile34Val (c.100A>G)** is classified **Uncertain significance** in DPM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-26). AlphaMissense: likely benign (0.0877); Very rare (popmax 0.00436%, nfe); Associated with congenital muscular dystrophy with intellectual disability and severe epilepsy.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1831510934 · 1 submitter · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.00436%, nfe)

## For patients & families {#patients}

This is a change in the DPM2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to congenital muscular dystrophy with intellectual disability and severe epilepsy.

*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 | DPM2 is a diagnostic-grade gene on 10 Genomics England panels |

**Commonly reported features of Congenital muscular dystrophy with intellectual disability and severe epilepsy** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Progressive microcephaly — Frequent (79-30%)
- Micrognathia — Frequent (79-30%)
- Osteopenia — Frequent (79-30%)
- Global developmental delay — Frequent (79-30%)
- Generalized hypotonia — Frequent (79-30%)
- Cerebellar hypoplasia — Frequent (79-30%)
- Absent speech — Frequent (79-30%)
- Failure to thrive — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0012416/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DPM2](https://sugi.bio/atlas/gene/DPM2/) |
| Protein change (HGVS p.) | p.Ile34Val |
| Coding change (HGVS c.) | c.100A>G |
| MANE Select transcript | [NM_003863](https://www.ncbi.nlm.nih.gov/nuccore/NM_003863) |
| dbSNP | [rs1831510934](https://www.ncbi.nlm.nih.gov/snp/rs1831510934/) |
| Variant type | single nucleotide variant |
| Location | chr9:127936649-127936649 (GRCh38) |
| ClinVar | [VCV1980382](https://www.ncbi.nlm.nih.gov/clinvar/variation/1980382/) |

**All HGVS expressions:** `NC_000009.11:g.130698928T>C`, `NC_000009.12:g.127936649T>C`, `NG_032927.1:g.6836A>G`, `NM_001378437.1:c.10A>G`, `NM_003863.4:c.100A>G`, `NR_165631.1:n.257A>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0877)
- REVEL 0.174 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.405 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 6.111, GERP 2.31, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 20.8**. 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 0.91** across the covering region of the MANE Select transcript (127,935,725–127,937,820), spanning 2,095 bp. Chi-square p 0.35. 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 (T>A, Δ0.23 acceptor 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 **0.00436%** (nfe) · FAF95 0.00334% · FAF99 0.00301% · 49/1,123,472 in the highest group · 49/1,498,056 alleles overall — very rare (popmax 0.00436%, 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}

**DPM2** population constraint: LOEUF 1.274, pLI 0.013762, missense-Z 0.045509. *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 muscular dystrophy with intellectual disability and severe epilepsy** — Moderate (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 91.96, 85% of residues very-high.

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

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

**Disease mechanism (Reactome):** DPM2 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}

DPM2 participates in **6 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 |
| [Synthesis of glycosylphosphatidylinositol (GPI)](https://reactome.org/content/detail/R-HSA-162710) | curated |

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

**Molecular function:** enzyme activator activity.

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

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-03-26.

**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 | 2022-03-26 |

## Associated conditions {#conditions}

[congenital muscular dystrophy with intellectual disability and severe epilepsy](https://sugi.bio/atlas/disease/congenital-muscular-dystrophy-with-intellectual-disability-and-severe-epilepsy/).

**Reported phenotype names (ClinVar):** Congenital muscular dystrophy with intellectual disability and severe epilepsy, CDG Iu, Congenital disorder of glycosylation type 1u.

## Similar variants {#similar}

Related DPM2 variant pages (same residue, condition, or type): [DPM2 p.Ile34=](/variant/dpm2-p-ile34), [DPM2 p.Arg47Ter](/variant/dpm2-p-arg47ter), [DPM2 p.Ala52Thr](/variant/dpm2-p-ala52thr), [DPM2 p.Leu30Val](/variant/dpm2-p-leu30val), [DPM2 p.Leu62Val](/variant/dpm2-p-leu62val), [DPM2 p.Tyr43His](/variant/dpm2-p-tyr43his), [DPM2 p.Val51Ile](/variant/dpm2-p-val51ile), [DPM2 c.3+12A>G](/variant/dpm2-c-3-plus-12a-g).

### 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 1980382). 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.*