# NM_000445.5(PLEC):c.6G>A (p.Ser2=)

https://sugi.bio/variant/plec-p-ser2

## Summary

**PLEC p.Ser2= (c.6G>A)** is classified **Likely benign** in PLEC (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-23). Ultra-rare (popmax 0.0535%, eas); Associated with epidermolysis bullosa simplex 5A, Ogna type.

**At a glance:** Likely benign · review: Single submitter · rsID rs782622551 · 1 submitter · 5 linked conditions · ultra-rare (popmax 0.0535%, eas)

## For patients & families {#patients}

This is a change in the PLEC gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to epidermolysis bullosa simplex 5A, Ogna type.

*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 dominant |
| 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 PLEC-related intermediate epidermolysis bullosa simplex without extracutaneous involvement** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Palmoplantar keratoderma — Frequent (79-30%)
- Fragile skin — Frequent (79-30%)
- Hypermelanotic macule — Frequent (79-30%)
- Palmoplantar blistering — Frequent (79-30%)
- Abnormal blistering of the skin — Frequent (79-30%)
- Hypopigmented macule — Frequent (79-30%)
- Acral blistering — Frequent (79-30%)
- Skin erosion — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0002148/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.Ser2= |
| Coding change (HGVS c.) | c.6G>A |
| MANE Select transcript | [NM_201384](https://www.ncbi.nlm.nih.gov/nuccore/NM_201384) (variant reported on NM_000445) |
| dbSNP | [rs782622551](https://www.ncbi.nlm.nih.gov/snp/rs782622551/) |
| Variant type | single nucleotide variant |
| Location | chr8:143975364-143975364 (GRCh38) |
| ClinVar | [VCV539056](https://www.ncbi.nlm.nih.gov/clinvar/variation/539056/) |

**All HGVS expressions:** `NC_000008.10:g.145049532C>T`, `NC_000008.11:g.143975364C>T`, `NG_012492.1:g.6382G>A`, `NM_000445.5:c.6G>A`, `NM_001410941.1:c.6G>A`

## 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 -9.957, GERP -3.69 — fast-evolving / accelerated position
- CADD: **PHRED 1.637**. 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 **0.0535%** (eas) · FAF95 0.0368% · FAF99 0.0313% · 24/44,882 in the highest group · 32/1,608,176 alleles overall — ultra-rare (popmax 0.0535%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.0535% | 1,870 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,428 |
| South Asian | 0.0011% | 91,084 |
| European (non-Finnish) | 0.000508% | 196,659 |

*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 **2** 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.Ser2= 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}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-05-23.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-05-23 |

## Associated conditions {#conditions}

[epidermolysis bullosa simplex 5A, Ogna type](https://sugi.bio/atlas/disease/epidermolysis-bullosa-simplex-5a-ogna-type/), [epidermolysis bullosa simplex 5B, with muscular dystrophy](https://sugi.bio/atlas/disease/epidermolysis-bullosa-simplex-5b-with-muscular-dystrophy/), [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, Ogna type, Autosomal recessive limb-girdle muscular dystrophy type 2Q, Epidermolysis bullosa simplex 5B, with muscular dystrophy, Epidermolysis bullosa simplex 5C, with pyloric atresia, Epidermolysis bullosa simplex with nail dystrophy, Pidermolysis bullosa simplex 5A, Ogna type, EPIDERMOLYSIS BULLOSA SIMPLEX 5A, OGNA TYPE, PLEC-Related Epidermolysis Bullosa with Pyloric Atresia, Epidermolysis bullosa simplex with pyloric atresia, PLEC1-Related Epidermolysis Bullosa with Pyloric Atresia.

## Similar variants {#similar}

Related PLEC variant pages (same residue, condition, or type): [PLEC p.Ala2Val](/variant/plec-p-ala2val), [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 539056). 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.*