# NM_201384.3(PLEC):c.10473C>T (p.Arg3491=)

https://sugi.bio/variant/plec-p-arg3491

## Summary

**PLEC p.Arg3491= (c.10473C>T)** is classified **Likely benign** in PLEC (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-06). Ultra-rare (popmax 0.025%, amr); Associated with autosomal recessive limb-girdle muscular dystrophy type 2Q.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs112569051 · 3 submitters · 5 linked conditions · ultra-rare (popmax 0.025%, amr)

## For patients & families {#patients}

This is a change in the PLEC gene that is classified as likely benign — not considered disease-causing, submitted by 3 submitters, and is linked to autosomal recessive limb-girdle muscular dystrophy type 2Q.

*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 |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | PLEC is a diagnostic-grade gene on 10 Genomics England panels |

**Commonly reported features of Plectin-related limb-girdle muscular dystrophy R17** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Progressive proximal muscle weakness — Very frequent (99-80%)
- Frequent falls — Frequent (79-30%)
- Loss of ambulation — Frequent (79-30%)
- Skeletal muscle atrophy — Frequent (79-30%)
- Elevated circulating creatine kinase concentration — Frequent (79-30%)
- Limb-girdle muscle weakness — Frequent (79-30%)
- Gowers sign — Frequent (79-30%)
- EMG: myopathic abnormalities — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0012542/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.Arg3491= |
| Coding change (HGVS c.) | c.10473C>T |
| MANE Select transcript | [NM_201384](https://www.ncbi.nlm.nih.gov/nuccore/NM_201384) |
| dbSNP | [rs112569051](https://www.ncbi.nlm.nih.gov/snp/rs112569051/) |
| Variant type | single nucleotide variant |
| Location | chr8:143919348-143919348 (GRCh38) |
| ClinVar | [VCV387673](https://www.ncbi.nlm.nih.gov/clinvar/variation/387673/) |

**All HGVS expressions:** `NC_000008.10:g.144993516G>A`, `NC_000008.11:g.143919348G>A`, `NG_012492.1:g.62398C>T`, `NM_000445.5:c.10554C>T`, `NM_201378.4:c.10431C>T`, `NM_201379.3:c.10407C>T`, `NM_201380.4:c.10884C>T`, `NM_201381.3:c.10377C>T`, `NM_201382.4:c.10473C>T`, `NM_201383.3:c.10485C>T`, `NM_201384.3:c.10473C>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 -7.345 — fast-evolving / accelerated position
- CADD: **PHRED 0.134**. 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** — 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%** (amr) · FAF95 0.0153% · FAF99 0.0124% · 15/60,030 in the highest group · 79/1,613,886 alleles overall — ultra-rare (popmax 0.025%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.025% | 4,002 |
| African / African-American | 0.012% | 8,340 |
| Remaining individuals (not grpmax-eligible) | 0.0096% | 10,417 |
| Finnish (not grpmax-eligible) | 0.00628% | 15,926 |
| South Asian | 0.00439% | 22,773 |
| European (non-Finnish) | 0.00347% | 28,781 |

*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 **3491** lies in the 'required for interaction with intermediate filament proteins' region; the 'globular 2' 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.Arg3491= 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}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-09-06.

**Submitter consensus:** unanimous (3/3 Likely benign).

**Submission history:** 3 submissions (2016–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-09-06 |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2016-08-05 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-10-03 |

## Associated conditions {#conditions}

[autosomal recessive limb-girdle muscular dystrophy type 2Q](https://sugi.bio/atlas/disease/autosomal-recessive-limb-girdle-muscular-dystrophy-type-2q/), [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/), [epidermolysis bullosa simplex with nail dystrophy](https://sugi.bio/atlas/disease/epidermolysis-bullosa-simplex-with-nail-dystrophy/).

**Reported phenotype names (ClinVar):** Autosomal recessive limb-girdle muscular dystrophy type 2Q, not specified, Epidermolysis bullosa simplex 5B, with muscular dystrophy, Epidermolysis bullosa simplex 5C, with pyloric atresia, Epidermolysis bullosa simplex with nail dystrophy, Epidermolysis bullosa simplex, Ogna type, MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 17, PLEC1-Related Epidermolysis Bullosa with Pyloric Atresia, 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.Arg3491Cys](/variant/plec-p-arg3491cys), [PLEC p.Arg3491His](/variant/plec-p-arg3491his), [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).

### 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 387673). 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.*