# NM_001927.4(DES):c.893C>T (p.Ser298Leu)

https://sugi.bio/variant/des-p-ser298leu

## Summary

**DES p.Ser298Leu (c.893C>T)** is classified **Conflicting classifications of pathogenicity** in DES (ClinVar, Conflicting submitters, 13 submitters; last evaluated 2026-01-28). AlphaMissense: ambiguous (0.5321); Ultra-rare (popmax 0.0225%, nfe); Associated with Cardiovascular phenotype.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs62636491 · 13 submitters · 6 linked conditions · AlphaMissense ambiguous · ultra-rare (popmax 0.0225%, nfe)

## For patients & families {#patients}

This is a change in the DES gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 13 submitters, and is linked to Cardiovascular phenotype.

*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.Ser298Leu |
| Coding change (HGVS c.) | c.893C>T |
| MANE Select transcript | [NM_001927](https://www.ncbi.nlm.nih.gov/nuccore/NM_001927) |
| dbSNP | [rs62636491](https://www.ncbi.nlm.nih.gov/snp/rs62636491/) |
| Variant type | single nucleotide variant |
| Location | chr2:219420652-219420652 (GRCh38) |
| ClinVar | [VCV66423](https://www.ncbi.nlm.nih.gov/clinvar/variation/66423/) |

**All HGVS expressions:** `LRG_380:g.7276C>T`, `LRG_380t1:c.893C>T`, `NC_000002.11:g.220285374C>T`, `NC_000002.12:g.219420652C>T`, `NG_008043.1:g.7276C>T`, `NM_001927.4:c.893C>T`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense makes no call; REVEL calls this damaging; SaProt does not; AlphaMissense makes no call — descriptive only.

- AlphaMissense **ambiguous** (0.5321) — no call either way
- REVEL 0.814 (moderately pathogenic-leaning)
- SaProt LLR -9.439 (tolerated)
- → **In-silico consensus:** REVEL calls this damaging; SaProt does not; AlphaMissense makes no call
- Conservation: phyloP 7.719, GERP 1.72, phastCons 1 — highly conserved
- CADD: **PHRED 33.0**. 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 (gnomAD v4.1): grpmax **0.0225%** (nfe) · FAF95 0.0203% · FAF99 0.0194% · 266/1,180,022 in the highest group · 287/1,613,856 alleles overall — ultra-rare (popmax 0.0225%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.0225% | 4,436 |
| Middle Eastern | 0.0164% | 6,082 |
| African / African-American | 0.0147% | 6,807 |
| Remaining individuals (not grpmax-eligible) | 0.0112% | 8,926 |
| Admixed American | 0.00333% | 29,993 |

*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 **298** lies in the 'coil 2b' region; the if rod domain; the 'interaction with neb' 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.Ser298Leu falls in the coil 2b 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-01-28.

**Submitter consensus:** conflicting (11 Uncertain significance, 2 Benign, 1 Likely pathogenic, 1 not provided).

**Submission history:** 15 submissions (2015–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital | Likely pathogenic | no assertion criteria provided | clinical testing | 2019-01-03 |
| Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-04-09 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-08-14 |
| Dasa | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-05-06 |
| Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Uncertain significance | criteria provided, single submitter | research | 2018-04-05 |
| Athena Diagnostics | Uncertain significance | criteria provided, single submitter | clinical testing | 2020-03-18 |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2019-04-11 |
| Eurofins Ntd Llc (ga) | Uncertain significance | criteria provided, single submitter | clinical testing | 2015-09-11 |
| Revvity Omics, Revvity | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-08-19 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2026-01-28 |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-10-01 |
| Epithelial Biology;  Institute of Medical Biology, Singapore | not provided | no classification provided | not provided |  |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2017-04-27 |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2017-04-27 |

## Associated conditions {#conditions}

[Cardiovascular phenotype](https://sugi.bio/atlas/disease/cardiovascular-phenotype/), [cardiomyopathy](https://sugi.bio/atlas/disease/cardiomyopathy/), [dilated cardiomyopathy](https://sugi.bio/atlas/disease/dilated-cardiomyopathy/), [neurogenic scapuloperoneal syndrome, Kaeser type](https://sugi.bio/atlas/disease/neurogenic-scapuloperoneal-syndrome-kaeser-type/), [myofibrillar myopathy 1](https://sugi.bio/atlas/disease/myofibrillar-myopathy-1/), [dilated cardiomyopathy 1I](https://sugi.bio/atlas/disease/dilated-cardiomyopathy-1i/).

**Reported phenotype names (ClinVar):** Cardiovascular phenotype, not provided, Primary dilated cardiomyopathy, Desmin-related myofibrillar myopathy, Cardiomyopathy, Dilated cardiomyopathy 1I, Neurogenic scapuloperoneal syndrome, Kaeser type, Desminopathy, 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.Ser298=](/variant/des-p-ser298), [DES p.Ser298Thr](/variant/des-p-ser298thr), [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).

### 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 66423). 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.*