# NM_024312.5(GNPTAB):c.3014_3018dup (p.Pro1007fs)

https://sugi.bio/variant/gnptab-p-pro1007fs

## Summary

**GNPTAB p.Pro1007fs (c.3014_3018dup)** is classified **Pathogenic** in GNPTAB (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-06). No gnomAD frequency available for this variant; Associated with mucolipidosis type III, alpha/beta.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2547954355 · 1 submitter · 2 linked conditions · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the GNPTAB gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to mucolipidosis type III, alpha/beta.

*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 |
| Prevalence | 1-9 / 1 000 000 (Europe) |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | GNPTAB is a diagnostic-grade gene on 15 Genomics England panels |

**Commonly reported features of Mucolipidosis type III** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Prominent occiput — Very frequent (99-80%)
- Visual impairment — Very frequent (99-80%)
- Joint stiffness — Very frequent (99-80%)
- Deficiency of N-acetylglucosamine-1-phosphotransferase — Very frequent (99-80%)
- Abnormality of the hip bone — Very frequent (99-80%)
- Abnormal form of the vertebral bodies — Very frequent (99-80%)
- Short stature — Very frequent (99-80%)
- Craniofacial hyperostosis — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017704/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [GNPTAB](https://sugi.bio/atlas/gene/GNPTAB/) |
| Protein change (HGVS p.) | p.Pro1007fs |
| Coding change (HGVS c.) | c.3014_3018dup |
| MANE Select transcript | [NM_024312](https://www.ncbi.nlm.nih.gov/nuccore/NM_024312) |
| dbSNP | [rs2547954355](https://www.ncbi.nlm.nih.gov/snp/rs2547954355/) |
| Variant type | Microsatellite |
| Location | chr12:101761243-101761244 (GRCh38) |
| ClinVar | [VCV2014582](https://www.ncbi.nlm.nih.gov/clinvar/variation/2014582/) |

**All HGVS expressions:** `NC_000012.11:g.102155024GCACT[3]`, `NC_000012.12:g.101761246GCACT[3]`, `NG_021243.1:g.74615TGCAG[3]`, `NM_024312.5:c.3014_3018dup`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 11.852, GERP 1.9, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.8, pLI 1.5001e-13. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 15 of 21**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no microsatellite variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**GNPTAB** population constraint: LOEUF 0.8, pLI 1.5001e-13, missense-Z 2.0514. *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):

- **GNPTAB-mucolipidosis** — Definitive (AR)

## Protein context {#protein}

Residue **1007** lies in a UniProt-annotated variant site (in mliiia); the ef-hand domain.

AlphaFold model confidence (whole protein): pLDDT 72.15, 24% of residues very-high.

**5 experimental structure(s)** (PDB): [2N6D](https://www.rcsb.org/structure/2N6D), [7S05](https://www.rcsb.org/structure/7S05), [7S06](https://www.rcsb.org/structure/7S06), [9BGF](https://www.rcsb.org/structure/9BGF), [9BGG](https://www.rcsb.org/structure/9BGG).

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

*Describes the biological roles of GNPTAB (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:** GNPTAB's established molecular role includes UDP-N-acetylglucosamine-lysosomal-enzyme N-acetylglucosaminephosphotransferase activity. p.Pro1007fs falls in the ef-hand domain.


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

**Molecular function:** UDP-N-acetylglucosamine-lysosomal-enzyme N-acetylglucosaminephosphotransferase activity.

**Biological process:** lysosome organization, N-glycan processing to lysosome, carbohydrate phosphorylation.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-07-06.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2022-07-06 |

## Associated conditions {#conditions}

[mucolipidosis type III, alpha/beta](https://sugi.bio/atlas/disease/mucolipidosis-type-iii-alpha-beta/), [mucolipidosis type II](https://sugi.bio/atlas/disease/mucolipidosis-type-ii/).

**Reported phenotype names (ClinVar):** Pseudo-Hurler polydystrophy, Mucolipidosis type II, MUCOLIPIDOSIS IIIA, ML III, ML III ALPHA/BETA, Type III Mucolipidosis, ML IIIA, Mucolipidosis III Alpha/Beta, Mucolipidosis II Alpha/Beta, ML II ALPHA/BETA.

## Similar variants {#similar}

Related GNPTAB variant pages (same residue, condition, or type): [GNPTAB p.Asn859fs](/variant/gnptab-p-asn859fs), [GNPTAB p.Glu1187fs](/variant/gnptab-p-glu1187fs), [GNPTAB p.Glu127fs](/variant/gnptab-p-glu127fs), [GNPTAB p.Glu833fs](/variant/gnptab-p-glu833fs), [GNPTAB p.Leu1168fs](/variant/gnptab-p-leu1168fs), [GNPTAB p.Lys850fs](/variant/gnptab-p-lys850fs), [GNPTAB p.Met957fs](/variant/gnptab-p-met957fs), [GNPTAB p.Phe53fs](/variant/gnptab-p-phe53fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2026-10-14); 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 2014582). 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.*