# NM_201384.3(PLEC):c.6416G>A (p.Arg2139His)

https://sugi.bio/variant/plec-p-arg2139his

## Summary

**PLEC p.Arg2139His (c.6416G>A)** is classified **Conflicting classifications of pathogenicity** in PLEC (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2025-11-24). AlphaMissense: likely benign (0.2204); Ultra-rare (popmax 0.025%, nfe); Associated with epidermolysis bullosa simplex 5C, with pyloric atresia.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs372652727 · 8 submitters · 5 linked conditions · AlphaMissense likely benign · ultra-rare (popmax 0.025%, nfe)

## 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 8 submitters, and is linked to epidermolysis bullosa simplex 5C, with pyloric atresia.

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

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

- Abnormality of the urinary system — Frequent (79-30%)
- Fragile skin — Frequent (79-30%)
- Aplasia cutis congenita — Frequent (79-30%)
- Vomiting — Frequent (79-30%)
- Elevated circulating creatine kinase concentration — Frequent (79-30%)
- Abdominal distention — Frequent (79-30%)
- Junctional split — Frequent (79-30%)
- Congenital pyloric atresia — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0016991/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.Arg2139His |
| Coding change (HGVS c.) | c.6416G>A |
| MANE Select transcript | [NM_201384](https://www.ncbi.nlm.nih.gov/nuccore/NM_201384) |
| dbSNP | [rs372652727](https://www.ncbi.nlm.nih.gov/snp/rs372652727/) |
| Variant type | single nucleotide variant |
| Location | chr8:143923513-143923513 (GRCh38) |
| ClinVar | [VCV471631](https://www.ncbi.nlm.nih.gov/clinvar/variation/471631/) |

**All HGVS expressions:** `NC_000008.10:g.144997681C>T`, `NC_000008.11:g.143923513C>T`, `NG_012492.1:g.58233G>A`, `NM_000445.5:c.6497G>A`, `NM_201378.4:c.6374G>A`, `NM_201379.3:c.6350G>A`, `NM_201380.4:c.6827G>A`, `NM_201381.3:c.6320G>A`, `NM_201382.4:c.6416G>A`, `NM_201383.3:c.6428G>A`, `NM_201384.3:c.6416G>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.2204)
- REVEL 0.383 (indeterminate)
- Conservation: phyloP 5.879, phastCons 1 — highly conserved (differs from AlphaMissense)
- **SaProt:** not scored — SaProt is structure-aware and AlphaFold DB has no model for this protein. That is a property of the dataset, not of the variant, and is not evidence either way.
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **R2276H** vs ClinVar **R2139H**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- CADD: **PHRED 24.7**. 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 1.08** across the covering region of the MANE Select transcript (143,918,174–143,935,987), spanning 17,813 bp. Chi-square p 4.9e-10. 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 **0.025%** (nfe) · FAF95 0.0227% · FAF99 0.0218% · 294/1,174,718 in the highest group · 318/1,596,442 alleles overall — ultra-rare (popmax 0.025%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.025% | 3,996 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.017% | 5,878 |
| Middle Eastern | 0.0166% | 6,010 |
| Remaining individuals (not grpmax-eligible) | 0.0129% | 7,756 |
| East Asian | 0.0112% | 8,947 |
| Admixed American | 0.0067% | 14,928 |
| African / African-American | 0.00134% | 74,688 |

*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}


**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.Arg2139His falls in the required for interaction with intermediate filament proteins 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-11-24.

**Submitter consensus:** conflicting (7 Uncertain significance, 1 Likely benign).

**Submission history:** 8 submissions (2017–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Department of Pathology and Laboratory Medicine, Sinai Health System | Uncertain significance | no assertion criteria provided | clinical testing |  |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2020-07-22 |
| PreventionGenetics, part of Exact Sciences | Uncertain significance | no assertion criteria provided | clinical testing | 2024-08-12 |
| Eurofins Ntd Llc (ga) | Uncertain significance | criteria provided, single submitter | clinical testing | 2017-05-23 |
| Revvity Omics, Revvity | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-02-13 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-11-24 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-11-19 |
| CeGaT Center for Human Genetics Tuebingen | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-12-01 |

## Associated conditions {#conditions}

[epidermolysis bullosa simplex 5C, with pyloric atresia](https://sugi.bio/atlas/disease/epidermolysis-bullosa-simplex-5c-with-pyloric-atresia/), [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/), [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 5C, with pyloric atresia, Autosomal recessive limb-girdle muscular dystrophy type 2Q, Epidermolysis bullosa simplex 5B, with muscular dystrophy, Epidermolysis bullosa simplex with nail dystrophy, Epidermolysis bullosa simplex, Ogna type, not provided, Inborn genetic diseases, PLEC-related disorder, none provided, PLEC1-Related Epidermolysis Bullosa with Pyloric Atresia.

## Similar variants {#similar}

Related PLEC variant pages (same residue, condition, or type): [PLEC p.Arg2139Cys](/variant/plec-p-arg2139cys), [PLEC p.Arg2139=](/variant/plec-p-arg2139), [PLEC p.Arg2139Leu](/variant/plec-p-arg2139leu), [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).

### 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 471631). 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.*