# NM_201384.3(PLEC):c.789C>T (p.Pro263=)

https://sugi.bio/variant/plec-p-pro263

## Summary

**PLEC p.Pro263= (c.789C>T)** is classified **Conflicting classifications of pathogenicity** in PLEC (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-11-05). Very rare (popmax 0.00445%, eas); Associated with epidermolysis bullosa simplex 5B, with muscular dystrophy.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs782100354 · 2 submitters · 5 linked conditions · very rare (popmax 0.00445%, eas)

## For patients & families {#patients}

This is a change in the PLEC gene that is of uncertain or conflicting significance (submitters disagree on it), 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.Pro263= |
| Coding change (HGVS c.) | c.789C>T |
| MANE Select transcript | [NM_201384](https://www.ncbi.nlm.nih.gov/nuccore/NM_201384) |
| dbSNP | [rs782100354](https://www.ncbi.nlm.nih.gov/snp/rs782100354/) |
| Variant type | single nucleotide variant |
| Location | chr8:143935047-143935047 (GRCh38) |
| ClinVar | [VCV1578307](https://www.ncbi.nlm.nih.gov/clinvar/variation/1578307/) |

**All HGVS expressions:** `NC_000008.10:g.145009215G>A`, `NC_000008.11:g.143935047G>A`, `NG_012492.1:g.46699C>T`, `NM_000445.3:c.870C>T`, `NM_000445.5:c.870C>T`, `NM_201378.4:c.747C>T`, `NM_201379.3:c.723C>T`, `NM_201380.4:c.1200C>T`, `NM_201381.3:c.693C>T`, `NM_201382.4:c.789C>T`, `NM_201383.3:c.801C>T`, `NM_201384.3:c.789C>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 0.215, phastCons 0.933 — weakly conserved position
- CADD: **PHRED 9.628**. 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: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for PLEC (1,435 scored positions, the nearest 10 bases away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency (gnomAD v4.1): grpmax **0.00445%** (eas) · FAF95 0.000878% · FAF99 0.000717% · 2/44,894 in the highest group · 21/1,612,718 alleles overall — very rare (popmax 0.00445%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.00445% | 22,447 |
| South Asian | 0.0022% | 45,547 |
| European (non-Finnish) | 0.00144% | 69,408 |

*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 **263** lies in the calponin-homology (ch) 1 domain; an α-helix; the 'globular 1' region; the 'actin-binding' 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.Pro263= falls in the calponin-homology (ch) 1 domain.


### 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2024-11-05.

**Submitter consensus:** conflicting (1 Uncertain significance, 1 Likely benign).

**Submission history:** 2 submissions (2019–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Revvity Omics, Revvity | Uncertain significance | criteria provided, single submitter | clinical testing | 2019-02-22 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-05 |

## 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, not provided, Epidermolysis bullosa simplex with muscular dystrophy, EPIDERMOLYSIS BULLOSA SIMPLEX AND LIMB-GIRDLE MUSCULAR DYSTROPHY, EPIDERMOLYSIS BULLOSA SIMPLEX 5A, OGNA TYPE, Pidermolysis bullosa simplex 5A, Ogna type.

## Similar variants {#similar}

Related PLEC variant pages (same residue, condition, or type): [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), [PLEC p.Gln1591Ter](/variant/plec-p-gln1591ter).

### 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 1578307). 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.*