# NM_013382.7(POMT2):c.1195C>T (p.Pro399Ser)

https://sugi.bio/variant/pomt2-p-pro399ser

## Summary

**POMT2 p.Pro399Ser (c.1195C>T)** is classified **Likely benign** in POMT2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-23). AlphaMissense: likely benign (0.0775); Very rare (popmax 0.00988%, sas); Associated with muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A2.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs200821647 · 2 submitters · 3 linked conditions · AlphaMissense likely benign · very rare (popmax 0.00988%, sas)

## For patients & families {#patients}

This is a change in the POMT2 gene that is classified as likely benign — not considered disease-causing, submitted by 2 submitters, and is linked to muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A2.

*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) | Antenatal, Infancy, Neonatal |
| Prevalence | <1 / 1 000 000 (United Kingdom) |
| Diagnostic panels | POMT2 is a diagnostic-grade gene on 19 Genomics England panels |

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

- Areflexia — Very frequent (99-80%)
- Pachygyria — Very frequent (99-80%)
- Cerebellar hypoplasia — Very frequent (99-80%)
- Muscle weakness — Very frequent (99-80%)
- Specific learning disability — Very frequent (99-80%)
- Lissencephaly — Very frequent (99-80%)
- Aplasia/Hypoplasia involving the skeletal musculature — Very frequent (99-80%)
- Ventriculomegaly — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015624/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [POMT2](https://sugi.bio/atlas/gene/POMT2/) |
| Protein change (HGVS p.) | p.Pro399Ser |
| Coding change (HGVS c.) | c.1195C>T |
| MANE Select transcript | [NM_013382](https://www.ncbi.nlm.nih.gov/nuccore/NM_013382) |
| dbSNP | [rs200821647](https://www.ncbi.nlm.nih.gov/snp/rs200821647/) |
| Variant type | single nucleotide variant |
| Location | chr14:77288820-77288820 (GRCh38) |
| ClinVar | [VCV1351615](https://www.ncbi.nlm.nih.gov/clinvar/variation/1351615/) |

**All HGVS expressions:** `LRG_844:g.37063C>T`, `NC_000014.8:g.77755163G>A`, `NC_000014.9:g.77288820G>A`, `NG_008897.1:g.37063C>T`, `NM_013382.7:c.1195C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.0775)
- REVEL 0.364 (indeterminate)
- SaProt LLR -8.653 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate
- Conservation: phyloP 11.83, GERP 1.75, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 21.9**. 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 0.98** across the covering region of the MANE Select transcript (77,277,379–77,320,681), spanning 43,302 bp. Chi-square p 0.62. 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 (gnomAD v4.1): grpmax **0.00988%** (sas) · FAF95 0.00514% · FAF99 0.00375% · 9/91,068 in the highest group · 255/1,613,666 alleles overall — very rare (popmax 0.00988%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.358% | 279 |
| South Asian (grpmax) | 0.00988% | 10,119 |
| Remaining individuals (not grpmax-eligible) | 0.0096% | 10,411 |
| European (non-Finnish) | 0.000932% | 107,265 |

Finnish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**POMT2** population constraint: LOEUF 0.944, pLI 3.911e-20, missense-Z -0.12705. *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):

- **myopathy caused by variation in POMT2** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 87.96, 68% of residues very-high.

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

*Describes the biological roles of POMT2 (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:** POMT2's established molecular role includes mannosyltransferase activity. In Reactome, POMT2 is annotated in disease pathway(s) including **Defective POMT1 causes MDDGA1, MDDGB1 and MDDGC1**, **Defective POMT2 causes MDDGA2, MDDGB2 and MDDGC2**.

**Disease mechanism (Reactome):** POMT2 loss or alteration is curated in [Defective POMT1 causes MDDGA1, MDDGB1 and MDDGC1](https://reactome.org/content/detail/R-HSA-5083633), [Defective POMT2 causes MDDGA2, MDDGB2 and MDDGC2](https://reactome.org/content/detail/R-HSA-5083629).

### Pathways affected {#pathways}

POMT2 participates in **6 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective POMT1 causes MDDGA1, MDDGB1 and MDDGC1](https://reactome.org/content/detail/R-HSA-5083633) | curated |
| ⚕ [Defective POMT2 causes MDDGA2, MDDGB2 and MDDGC2](https://reactome.org/content/detail/R-HSA-5083629) | curated |
| [DAG1 core M1 glycosylations](https://reactome.org/content/detail/R-HSA-8932506) | curated |
| [DAG1 core M2 glycosylations](https://reactome.org/content/detail/R-HSA-8932504) | curated |
| [DAG1 core M3 glycosylations](https://reactome.org/content/detail/R-HSA-8932505) | curated |
| [Regulation of CDH1 posttranslational processing and trafficking to plasma membrane](https://reactome.org/content/detail/R-HSA-9768727) | curated |

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

**Molecular function:** mannosyltransferase activity.

**Biological process:** protein O-linked glycosylation via mannose.

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-12-23.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 2 submissions (2024–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-12-23 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-08 |

## Associated conditions {#conditions}

[muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A2](https://sugi.bio/atlas/disease/muscular-dystrophy-dystroglycanopathy-congenital-with-brain-and-eye-anomalies-type-a2/), [muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B2](https://sugi.bio/atlas/disease/muscular-dystrophy-dystroglycanopathy-congenital-with-intellectual-disability-type-b2/), [autosomal recessive limb-girdle muscular dystrophy type 2N](https://sugi.bio/atlas/disease/autosomal-recessive-limb-girdle-muscular-dystrophy-type-2n/).

**Reported phenotype names (ClinVar):** Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A2, Autosomal recessive limb-girdle muscular dystrophy type 2N, Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B2, not specified, MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (CONGENITAL WITH BRAIN AND EYE ANOMALIES), TYPE A, 2, WALKER-WARBURG SYNDROME OR MUSCLE-EYE-BRAIN DISEASE, POMT2-RELATED, MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (CONGENITAL WITH IMPAIRED INTELLECTUAL DEVELOPMENT), TYPE B, 2, MUSCULAR DYSTROPHY, CONGENITAL, POMT2-RELATED, Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 2, MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY, LIMB-GIRDLE, POMT2-RELATED.

## Similar variants {#similar}

Related POMT2 variant pages (same residue, condition, or type): [POMT2 c.1006+1G>A](/variant/pomt2-c-1006-plus-1g-a), [POMT2 c.1184-1G>C](/variant/pomt2-c-1184-minus-1g-c), [POMT2 c.1254-2A>G](/variant/pomt2-c-1254-minus-2a-g), [POMT2 c.1333-14G>A](/variant/pomt2-c-1333-minus-14g-a), [POMT2 c.1786-2A>T](/variant/pomt2-c-1786-minus-2a-t), [POMT2 c.248+1G>A](/variant/pomt2-c-248-plus-1g-a), [POMT2 c.248+1G>C](/variant/pomt2-c-248-plus-1g-c), [POMT2 c.248+1G>T](/variant/pomt2-c-248-plus-1g-t).

### 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 1351615). 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.*