# NM_000445.5(PLEC):c.88C>T (p.Pro30Ser)

https://sugi.bio/variant/plec-p-pro30ser

## Summary

**PLEC p.Pro30Ser (c.88C>T)** is classified **Uncertain significance** in PLEC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-26). Very rare (popmax 8.47e-05%, nfe); Associated with epidermolysis bullosa simplex 5B, with muscular dystrophy.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs782457026 · 2 submitters · 5 linked conditions · very rare (popmax 8.47e-05%, nfe)

## For patients & families {#patients}

This is a change in the PLEC gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, and is linked to epidermolysis bullosa simplex 5B, with muscular dystrophy.

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

**Commonly reported features of Epidermolysis bullosa simplex with muscular dystrophy** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Ophthalmoparesis — Very frequent (99-80%)
- Ophthalmoplegia — Very frequent (99-80%)
- Alopecia — Very frequent (99-80%)
- Hypoplastic fingernail — Very frequent (99-80%)
- Hyperconvex fingernails — Very frequent (99-80%)
- Mutism — Very frequent (99-80%)
- Aphasia — Very frequent (99-80%)
- Myopathy — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0002137/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PLEC](https://sugi.bio/atlas/gene/PLEC/) |
| Protein change (HGVS p.) | p.Pro30Ser |
| Coding change (HGVS c.) | c.88C>T |
| MANE Select transcript | [NM_201384](https://www.ncbi.nlm.nih.gov/nuccore/NM_201384) (variant reported on NM_000445) |
| dbSNP | [rs782457026](https://www.ncbi.nlm.nih.gov/snp/rs782457026/) |
| Variant type | single nucleotide variant |
| Location | chr8:143975282-143975282 (GRCh38) |
| ClinVar | [VCV2091023](https://www.ncbi.nlm.nih.gov/clinvar/variation/2091023/) |

**All HGVS expressions:** `NC_000008.10:g.145049450G>A`, `NC_000008.11:g.143975282G>A`, `NG_012492.1:g.6464C>T`, `NM_000445.5:c.88C>T`, `NM_001410941.1:c.88C>T`

## Computational & population evidence {#evidence}

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

- **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 11.31, GERP 1.92, phastCons 1 — highly conserved position (PP3-type support)
- 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.*
- SpliceAI: **not assessed** — this absence is genuinely unknown. Where a position sits between the lowest and the highest record the release holds for its gene, an absent score is a result and we state it as one; this position falls outside them, or the gene has no scored position at all, so that test did not reach here. It may lie outside the scored MANE transcript scope, or it may have been scored with all four deltas below Δ0.2 just past the last surviving record. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **8.47e-05%** (nfe) · 1/1,179,970 in the highest group · 2/1,610,008 alleles overall — very rare (popmax 8.47e-05%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.00167% | 59,986 |
| European (non-Finnish) (grpmax) | 8.47e-05% | 1,179,970 |

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}

**PLEC** population constraint: LOEUF 0.726, pLI 5.951e-44, missense-Z -2.7548. *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):

- **PLEC-related muscular dystrophy-epidermolysis bullosa simplex spectrum disorder** — Definitive (AR)

## Protein context {#protein}

Residue **30** lies in the 'globular 1' region.

**14 experimental structure(s)** (PDB): [1MB8](https://www.rcsb.org/structure/1MB8), [2N03](https://www.rcsb.org/structure/2N03), [2ODU](https://www.rcsb.org/structure/2ODU), [2ODV](https://www.rcsb.org/structure/2ODV), [3F7P](https://www.rcsb.org/structure/3F7P), [3PDY](https://www.rcsb.org/structure/3PDY) — incl. mutant structure 2ODV.

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

*Describes the biological roles of PLEC (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:** PLEC's established molecular role includes RNA binding. p.Pro30Ser falls in the globular 1 region.


### Pathways affected {#pathways}

PLEC participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Assembly of collagen fibrils and other multimeric structures](https://reactome.org/content/detail/R-HSA-2022090) | curated |
| [Caspase-mediated cleavage of cytoskeletal proteins](https://reactome.org/content/detail/R-HSA-264870) | curated |
| [Type I hemidesmosome assembly](https://reactome.org/content/detail/R-HSA-446107) | curated |

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

**Molecular function:** RNA binding, structural constituent of muscle, ankyrin binding, cadherin binding.

**Biological process:** hemidesmosome assembly.

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-10-26.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2021–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-09-27 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-10-26 |

## Associated conditions {#conditions}

[epidermolysis bullosa simplex 5B, with muscular dystrophy](https://sugi.bio/atlas/disease/epidermolysis-bullosa-simplex-5b-with-muscular-dystrophy/), [epidermolysis bullosa simplex 5A, Ogna type](https://sugi.bio/atlas/disease/epidermolysis-bullosa-simplex-5a-ogna-type/), [epidermolysis bullosa simplex 5C, with pyloric atresia](https://sugi.bio/atlas/disease/epidermolysis-bullosa-simplex-5c-with-pyloric-atresia/), [autosomal recessive limb-girdle muscular dystrophy type 2Q](https://sugi.bio/atlas/disease/autosomal-recessive-limb-girdle-muscular-dystrophy-type-2q/), [epidermolysis bullosa simplex with nail dystrophy](https://sugi.bio/atlas/disease/epidermolysis-bullosa-simplex-with-nail-dystrophy/).

**Reported phenotype names (ClinVar):** Epidermolysis bullosa simplex 5B, with muscular dystrophy, Autosomal recessive limb-girdle muscular dystrophy type 2Q, Epidermolysis bullosa simplex 5C, with pyloric atresia, Epidermolysis bullosa simplex with nail dystrophy, Epidermolysis bullosa simplex, Ogna type, Inborn genetic diseases, Epidermolysis bullosa simplex with muscular dystrophy, EPIDERMOLYSIS BULLOSA SIMPLEX AND LIMB-GIRDLE MUSCULAR DYSTROPHY, PLEC-Related Epidermolysis Bullosa with Pyloric Atresia, Epidermolysis bullosa simplex with pyloric atresia.

## Similar variants {#similar}

Related PLEC variant pages (same residue, condition, or type): [PLEC p.Pro30=](/variant/plec-p-pro30), [PLEC p.Arg1490Ter](/variant/plec-p-arg1490ter), [PLEC p.Arg1973Trp](/variant/plec-p-arg1973trp), [PLEC p.Arg2027Ter](/variant/plec-p-arg2027ter), [PLEC p.Arg2292Ter](/variant/plec-p-arg2292ter), [PLEC p.Arg2324Ter](/variant/plec-p-arg2324ter), [PLEC p.Arg2394Ter](/variant/plec-p-arg2394ter), [PLEC p.Arg559Ter](/variant/plec-p-arg559ter).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 2091023). 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.*