# NM_001927.4(DES):c.36C>T (p.Ser12=)

https://sugi.bio/variant/des-p-ser12

## Summary

**DES p.Ser12= (c.36C>T)** is classified **Likely benign** in DES (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-22). Very rare (popmax 0.00034%, nfe); Associated with myofibrillar myopathy 1.

**At a glance:** Likely benign · review: Single submitter · rsID rs2545245519 · 1 submitter · 1 linked condition · very rare (popmax 0.00034%, nfe)

## For patients & families {#patients}

This is a change in the DES gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to myofibrillar myopathy 1.

*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, Autosomal recessive |
| Age of onset (of this condition) | Adolescent, Adult, Childhood, Infancy |
| Diagnostic panels | DES is a diagnostic-grade gene on 12 Genomics England panels |

**Commonly reported features of Desminopathy** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Progressive muscle weakness — Very frequent (99-80%)
- Axial muscle weakness — Very frequent (99-80%)
- Distal lower limb muscle weakness — Very frequent (99-80%)
- Gait disturbance — Frequent (79-30%)
- Congestive heart failure — Frequent (79-30%)
- Atrioventricular block — Frequent (79-30%)
- Loss of ambulation — Frequent (79-30%)
- Respiratory insufficiency due to muscle weakness — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0016870/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DES](https://sugi.bio/atlas/gene/DES/) |
| Protein change (HGVS p.) | p.Ser12= |
| Coding change (HGVS c.) | c.36C>T |
| MANE Select transcript | [NM_001927](https://www.ncbi.nlm.nih.gov/nuccore/NM_001927) |
| dbSNP | [rs2545245519](https://www.ncbi.nlm.nih.gov/snp/rs2545245519/) |
| Variant type | single nucleotide variant |
| Location | chr2:219418498-219418498 (GRCh38) |
| ClinVar | [VCV2167778](https://www.ncbi.nlm.nih.gov/clinvar/variation/2167778/) |

**All HGVS expressions:** `LRG_380:g.5122C>T`, `LRG_380t1:c.36C>T`, `NC_000002.11:g.220283220C>T`, `NC_000002.12:g.219418498C>T`, `NG_008043.1:g.5122C>T`, `NG_046330.1:g.18890C>T`, `NM_001382708.1:c.36C>T`, `NM_001382709.1:c.36C>T`, `NM_001382710.1:c.36C>T`, `NM_001382711.1:c.36C>T`, `NM_001382712.1:c.36C>T`, `NM_001382713.1:c.36C>T`, `NM_001927.4:c.36C>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 1.074, GERP -0.75, phastCons 1 — weakly conserved position
- CADD: **PHRED 13.49**. 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 **0.00034%** (nfe) · FAF95 8e-05% · FAF99 5.4e-05% · 4/1,177,110 in the highest group · 4/1,450,150 alleles overall — very rare (popmax 0.00034%, nfe).

*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}

**DES** population constraint: LOEUF 0.81, pLI 2.4033e-06, missense-Z 0.37093. *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):

- **dilated cardiomyopathy 1I** — Definitive (AD)
- **arrhythmogenic right ventricular cardiomyopathy** — Moderate (AD)

## Protein context {#protein}

Residue **12** lies in a modified residue (phosphoserine; by aurkb); the 'head' region.

AlphaFold model confidence (whole protein): pLDDT 77.73, 56% of residues very-high.

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

*Describes the biological roles of DES (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:** DES's established molecular role includes cytoskeletal protein binding. p.Ser12= falls in the head region.


### Pathways affected {#pathways}

DES participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Striated Muscle Contraction](https://reactome.org/content/detail/R-HSA-390522) | curated |

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

**Molecular function:** cytoskeletal protein binding, identical protein binding.

**Biological process:** intermediate filament organization.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-06-22.

**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 | 2022-06-22 |

## Associated conditions {#conditions}

[myofibrillar myopathy 1](https://sugi.bio/atlas/disease/myofibrillar-myopathy-1/).

**Reported phenotype names (ClinVar):** Desmin-related myofibrillar myopathy, Desminopathy, Desmin related myopathy (former name), Desmin storage myopathy (former name), MYOFIBRILLAR MYOPATHY WITH ARRHYTHMOGENIC RIGHT VENTRICULAR CARDIOMYOPATHY, DESMIN-RELATED MYOPATHY WITH ARRHYTHMOGENIC RIGHT VENTRICULAR CARDIOMYOPATHY, Myofibrillar myopathy 1.

## Same-residue context {#hotspot}

Residue **12** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [DES p.Ser12Phe](/variant/des-p-ser12phe). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related DES variant pages (same residue, condition, or type): [DES p.Ser12Phe](/variant/des-p-ser12phe), [DES c.1289-2A>G](/variant/des-c-1289-minus-2a-g), [DES c.579-2A>C](/variant/des-c-579-minus-2a-c), [DES c.735+1G>A](/variant/des-c-735-plus-1g-a), [DES c.735+1G>C](/variant/des-c-735-plus-1g-c), [DES c.735+3A>G](/variant/des-c-735-plus-3a-g), [DES p.Ala120Pro](/variant/des-p-ala120pro), [DES p.Ala285Val](/variant/des-p-ala285val).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2026-07-14); 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 2167778). 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.*