# NM_001927.4(DES):c.5G>T (p.Ser2Ile)

https://sugi.bio/variant/des-p-ser2ile

## Summary

**DES p.Ser2Ile (c.5G>T)** is classified **Pathogenic/Likely pathogenic** in DES (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-10-25). AlphaMissense: likely pathogenic (0.6127); No allele count reported in gnomAD v4.1 (AN 1,594,604); Associated with myofibrillar myopathy 1.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs58999456 · 4 submitters · 2 linked conditions · AlphaMissense likely pathogenic · no allele count reported in gnomAD v4.1 (AN 1,594,604)

## For patients & families {#patients}

This is a change in the DES gene that is considered likely disease-causing, submitted by 4 submitters, 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.Ser2Ile |
| Coding change (HGVS c.) | c.5G>T |
| MANE Select transcript | [NM_001927](https://www.ncbi.nlm.nih.gov/nuccore/NM_001927) |
| dbSNP | [rs58999456](https://www.ncbi.nlm.nih.gov/snp/rs58999456/) |
| Variant type | single nucleotide variant |
| Location | chr2:219418467-219418467 (GRCh38) |
| ClinVar | [VCV66414](https://www.ncbi.nlm.nih.gov/clinvar/variation/66414/) |

**All HGVS expressions:** `LRG_380:g.5091G>T`, `LRG_380t1:c.5G>T`, `NC_000002.11:g.220283189G>T`, `NC_000002.12:g.219418467G>T`, `NG_008043.1:g.5091G>T`, `NG_046330.1:g.18859G>T`, `NM_001927.4:c.5G>T`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.6127) — concordant with the pathogenic call
- REVEL 0.672 (pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -11.096 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 11.436, GERP 1.68, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 27.3**. 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 0.92** across the covering region of the MANE Select transcript (219,418,463–219,425,987), spanning 7,524 bp. Chi-square p 0.05. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code 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: **no allele count reported in gnomAD v4.1 (AN 1,594,604)** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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 **2** lies in the 'head' region; a UniProt-annotated variant site (in mfm1).

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.Ser2Ile 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}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-10-25.

**Submitter consensus:** conflicting (2 Pathogenic, 1 not provided, 1 Likely pathogenic).

**Submission history:** 4 submissions (2022–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Epithelial Biology;  Institute of Medical Biology, Singapore | not provided | no classification provided | not provided |  |
| Athena Diagnostics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2022-12-28 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-10-25 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2023-02-08 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Desmin-related myofibrillar myopathy, not provided, Primary familial dilated cardiomyopathy, 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, Familial dilated cardiomyopathy.

## Similar variants {#similar}

Related DES variant pages (same residue, condition, or type): [DES p.Ser2Asn](/variant/des-p-ser2asn), [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 2026-10-14); 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 66414). 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.*