# NM_001077365.2(POMT1):c.558G>A (p.Trp186Ter)

https://sugi.bio/variant/pomt1-p-trp186ter

## Summary

**POMT1 p.Trp186Ter (c.558G>A)** is classified **Pathogenic** in POMT1 (ClinVar, Single submitter, 2 submitters; last evaluated 2022-05-09). Absent from gnomAD v4.1; Associated with autosomal recessive limb-girdle muscular dystrophy type 2K.

**At a glance:** Pathogenic · review: Single submitter · rsID rs772370177 · 2 submitters · 4 linked conditions · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the POMT1 gene that is reported as disease-causing, but on limited review, submitted by 2 submitters, and is linked to autosomal recessive limb-girdle muscular dystrophy type 2K.

*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 / 1 000 000 (Europe) |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | POMT1 is a diagnostic-grade gene on 23 Genomics England panels |

**Commonly reported features of POMT1-related limb-girdle muscular dystrophy R11** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Difficulty climbing stairs — Very frequent (99-80%)
- Gait disturbance — Very frequent (99-80%)
- Microcephaly — Frequent (79-30%)
- Delayed speech and language development — Frequent (79-30%)
- Intellectual disability — Frequent (79-30%)
- Waddling gait — Frequent (79-30%)
- Lumbar hyperlordosis — Frequent (79-30%)
- Elevated circulating creatine kinase concentration — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0012535/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [POMT1](https://sugi.bio/atlas/gene/POMT1/) |
| Protein change (HGVS p.) | p.Trp186Ter |
| Coding change (HGVS c.) | c.558G>A |
| MANE Select transcript | [NM_001077365](https://www.ncbi.nlm.nih.gov/nuccore/NM_001077365) |
| dbSNP | [rs772370177](https://www.ncbi.nlm.nih.gov/snp/rs772370177/) |
| Variant type | single nucleotide variant |
| Location | chr9:131509761-131509761 (GRCh38) |
| ClinVar | [VCV212739](https://www.ncbi.nlm.nih.gov/clinvar/variation/212739/) |

**All HGVS expressions:** `LRG_842t1:c.558G>A`, `LRG_842t2:c.558G>A`, `NC_000009.11:g.134385148G>A`, `NC_000009.12:g.131509761G>A`, `NG_008896.1:g.11860G>A`, `NM_001077365.2:c.558G>A`, `NM_001077366.2:c.396G>A`, `NM_001136113.2:c.558G>A`, `NM_001136114.2:c.207G>A`, `NM_001353193.2:c.558G>A`, `NM_001353194.2:c.396G>A`, `NM_001353195.2:c.207G>A`, `NM_001353196.2:c.468G>A`, `NM_001353197.2:c.396G>A`, `NM_001353198.2:c.396G>A`, `NM_001353199.2:c.207G>A`, `NM_001353200.2:c.102G>A`, `NM_001374689.1:c.396G>A`, `NM_001374690.1:c.558G>A`, `NM_001374691.1:c.207G>A`, `NM_001374692.1:c.207G>A`, `NM_001374693.1:c.396G>A`, `NM_001374695.1:c.102G>A`, `NM_007171.4:c.558G>A`, `NR_148391.2:n.592G>A`, `NR_148392.2:n.744G>A`, `NR_148393.2:n.592G>A`, `NR_148394.2:n.480G>A`, `NR_148395.2:n.744G>A`, `NR_148396.2:n.373G>A`, `NR_148397.2:n.637G>A`, `NR_148398.2:n.592G>A`, `NR_148399.2:n.984G>A`, `NR_148400.2:n.578G>A`

## 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 11.696, GERP 2.24, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **nonsense (stop-gain)** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.002, pLI 7.2486e-26. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 7 of 20**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 41.0**. 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.*
- 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}

**POMT1** population constraint: LOEUF 1.002, pLI 7.2486e-26, missense-Z 1.1362; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity 0/3. *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 POMT1** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 88.09, 67% of residues very-high.

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

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

**Disease mechanism (Reactome):** POMT1 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}

POMT1 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}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-05-09.

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

**Submission history:** 2 submissions (2014–2022); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Knight Diagnostic Laboratories, Oregon Health and Sciences University | Likely pathogenic | no assertion criteria provided | clinical testing | 2014-07-29 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2022-05-09 |

## Associated conditions {#conditions}

[autosomal recessive limb-girdle muscular dystrophy type 2K](https://sugi.bio/atlas/disease/autosomal-recessive-limb-girdle-muscular-dystrophy-type-2k/), [muscular dystrophy-dystroglycanopathy, type A](https://sugi.bio/atlas/disease/muscular-dystrophy-dystroglycanopathy-type-a/), [muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1](https://sugi.bio/atlas/disease/muscular-dystrophy-dystroglycanopathy-congenital-with-brain-and-eye-anomalies-type-a1/), [muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B1](https://sugi.bio/atlas/disease/muscular-dystrophy-dystroglycanopathy-congenital-with-intellectual-disability-type-b1/).

**Reported phenotype names (ClinVar):** Autosomal recessive limb-girdle muscular dystrophy type 2K, Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1, Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B1, Walker-Warburg congenital muscular dystrophy, COD-MD SYNDROME, Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 1, WALKER-WARBURG SYNDROME OR MUSCLE-EYE-BRAIN DISEASE, POMT1-RELATED, Hydrocephalus, agyria and retinal dysplasia, Hard +/- E syndrome, Warburg syndrome.

## Similar variants {#similar}

Related POMT1 variant pages (same residue, condition, or type): [POMT1 p.Trp186Cys](/variant/pomt1-p-trp186cys), [POMT1 c.1175+1G>A](/variant/pomt1-c-1175-plus-1g-a), [POMT1 c.1176-2A>G](/variant/pomt1-c-1176-minus-2a-g), [POMT1 c.1272+1G>A](/variant/pomt1-c-1272-plus-1g-a), [POMT1 c.1272+2T>C](/variant/pomt1-c-1272-plus-2t-c), [POMT1 c.1698+1G>A](/variant/pomt1-c-1698-plus-1g-a), [POMT1 c.2004-1G>C](/variant/pomt1-c-2004-minus-1g-c), [POMT1 c.229+2T>C](/variant/pomt1-c-229-plus-2t-c).

### 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 212739). 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.*