# NM_001927.4(DES):c.38C>T (p.Ser13Phe)

https://sugi.bio/variant/des-p-ser13phe

## Summary

**DES p.Ser13Phe (c.38C>T)** is classified **Pathogenic** in DES (ClinVar, Multiple submitters, 10 submitters; last evaluated 2025-10-29). AlphaMissense: likely pathogenic (0.9569); Absent from gnomAD v4.1; Associated with DES-related disorders.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs62636495 · 10 submitters · 3 linked conditions · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the DES gene that is considered disease-causing, submitted by 10 submitters, and is linked to DES-related disorders.

*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.*

**Support & next steps:** [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.Ser13Phe |
| Coding change (HGVS c.) | c.38C>T |
| MANE Select transcript | [NM_001927](https://www.ncbi.nlm.nih.gov/nuccore/NM_001927) |
| dbSNP | [rs62636495](https://www.ncbi.nlm.nih.gov/snp/rs62636495/) |
| Variant type | single nucleotide variant |
| Location | chr2:219418500-219418500 (GRCh38) |
| ClinVar | [VCV44260](https://www.ncbi.nlm.nih.gov/clinvar/variation/44260/) |

**All HGVS expressions:** `LRG_380:g.5124C>T`, `LRG_380t1:c.38C>T`, `NC_000002.11:g.220283222C>T`, `NC_000002.12:g.219418500C>T`, `NG_008043.1:g.5124C>T`, `NG_046330.1:g.18892C>T`, `NM_001927.4:c.38C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9569) — concordant with the pathogenic call
- REVEL 0.926 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -13.081 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 7.401, GERP 0.5, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 27.8**. 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** — 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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 **13** lies in the 'head' region; a UniProt-annotated variant site (in mfm1; some patients manifest a severe cardiac phenotype with right ventricular predominance).

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.Ser13Phe 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** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-10-29.

**Submitter consensus:** conflicting (9 Pathogenic, 1 not provided).

**Submission history:** 10 submissions (2009–2025); 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 |  |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2009-11-01 |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Pathogenic | criteria provided, single submitter | clinical testing | 2011-09-07 |
| Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | Pathogenic | no assertion criteria provided | clinical testing |  |
| Baylor Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2013-11-26 |
| Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | Pathogenic | no assertion criteria provided | clinical testing |  |
| Clinical Genetics, Academic Medical Center | Pathogenic | no assertion criteria provided | clinical testing |  |
| Blueprint Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2021-03-08 |
| Eurofins Ntd Llc (ga) | Pathogenic | criteria provided, single submitter | clinical testing | 2017-03-02 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-10-29 |

## Associated conditions {#conditions}

[DES-related disorders](https://sugi.bio/atlas/disease/des-related-disorders/), [dilated cardiomyopathy](https://sugi.bio/atlas/disease/dilated-cardiomyopathy/), [myofibrillar myopathy 1](https://sugi.bio/atlas/disease/myofibrillar-myopathy-1/).

**Reported phenotype names (ClinVar):** DES-related disorders, Primary dilated cardiomyopathy, not provided, Desmin-related myofibrillar myopathy, Desminopathy, Desmin related myopathy (former name), Desmin storage myopathy (former name), Myofibrillar myopathy 1, MYOFIBRILLAR MYOPATHY WITH ARRHYTHMOGENIC RIGHT VENTRICULAR CARDIOMYOPATHY, DESMIN-RELATED MYOPATHY WITH ARRHYTHMOGENIC RIGHT VENTRICULAR CARDIOMYOPATHY.

## Similar variants {#similar}

Related DES variant pages (same residue, condition, or type): [DES p.Ser13Tyr](/variant/des-p-ser13tyr), [DES p.Ser13Pro](/variant/des-p-ser13pro), [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 c.736-1G>A](/variant/des-c-736-minus-1g-a).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 44260). 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.*