# NM_001077365.2(POMT1):c.558G>T (p.Trp186Cys)

https://sugi.bio/variant/pomt1-p-trp186cys

## Summary

**POMT1 p.Trp186Cys (c.558G>T)** is classified **Uncertain significance** in POMT1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-07-17). AlphaMissense: likely pathogenic (0.8193); Ultra-rare (popmax 0.0285%, sas); Associated with autosomal recessive limb-girdle muscular dystrophy type 2K.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs772370177 · 3 submitters · 3 linked conditions · AlphaMissense likely pathogenic · ultra-rare (popmax 0.0285%, sas)

## For patients & families {#patients}

This is a change in the POMT1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 3 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.Trp186Cys |
| Coding change (HGVS c.) | c.558G>T |
| 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 | [VCV2154108](https://www.ncbi.nlm.nih.gov/clinvar/variation/2154108/) |

**All HGVS expressions:** `LRG_842:g.11860G>T`, `LRG_842t1:c.558G>T`, `LRG_842t2:c.558G>T`, `NC_000009.11:g.134385148G>T`, `NC_000009.12:g.131509761G>T`, `NG_008896.2:g.11860G>T`, `NM_001077365.2:c.558G>T`, `NM_001077366.2:c.396G>T`, `NM_001136113.2:c.558G>T`, `NM_001136114.2:c.207G>T`, `NM_001353193.2:c.558G>T`, `NM_001353194.2:c.396G>T`, `NM_001353195.2:c.207G>T`, `NM_001353196.2:c.468G>T`, `NM_001353197.2:c.396G>T`, `NM_001353198.2:c.396G>T`, `NM_001353199.2:c.207G>T`, `NM_001353200.2:c.102G>T`, `NM_001374689.1:c.396G>T`, `NM_001374690.1:c.558G>T`, `NM_001374691.1:c.207G>T`, `NM_001374692.1:c.207G>T`, `NM_001374693.1:c.396G>T`, `NM_001374695.1:c.102G>T`, `NM_001411024.1:c.-579G>T`, `NM_007171.4:c.558G>T`, `NR_148391.2:n.592G>T`, `NR_148392.2:n.744G>T`, `NR_148393.2:n.592G>T`, `NR_148394.2:n.480G>T`, `NR_148395.2:n.744G>T`, `NR_148396.2:n.373G>T`, `NR_148397.2:n.637G>T`, `NR_148398.2:n.592G>T`, `NR_148399.2:n.984G>T`, `NR_148400.2:n.578G>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.8193)
- REVEL 0.875 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -13.907 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 11.696, GERP 2.24, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 32.0**. 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.*
- Regional missense constraint: **o/e 0.92** across the covering region of the MANE Select transcript (131,504,219–131,523,103), spanning 18,884 bp. Chi-square p 0.016. 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 **0.0285%** (sas) · FAF95 0.0199% · FAF99 0.0171% · 26/91,090 in the highest group · 26/1,461,886 alleles overall — ultra-rare (popmax 0.0285%, sas).

*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 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):

- **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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-07-17.

**Submitter consensus:** unanimous (3/3 Uncertain significance).

**Submission history:** 3 submissions (2022–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-05-22 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-07-17 |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-06-27 |

## 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 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 intellectual disability), type B1, Walker-Warburg congenital muscular dystrophy, not specified, not provided, AllHighlyPenetrant, MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 2K, MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (LIMB-GIRDLE), TYPE C, 1, MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (CONGENITAL WITH IMPAIRED INTELLECTUAL DEVELOPMENT), TYPE B, 1, MUSCULAR DYSTROPHY, CONGENITAL, POMT1-RELATED.

## Same-residue context {#hotspot}

Residue **186** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [POMT1 p.Trp186Ter](/variant/pomt1-p-trp186ter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related POMT1 variant pages (same residue, condition, or type): [POMT1 p.Trp186Ter](/variant/pomt1-p-trp186ter), [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.229+2T>C](/variant/pomt1-c-229-plus-2t-c), [POMT1 c.280+1G>T](/variant/pomt1-c-280-plus-1g-t).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2154108). 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.*