# NM_001927.4(DES):c.817G>C (p.Ala273Pro)

https://sugi.bio/variant/des-p-ala273pro

## Summary

**DES p.Ala273Pro (c.817G>C)** is classified **Uncertain significance** in DES (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-25). AlphaMissense: likely pathogenic (0.9991); Absent from gnomAD v4.1; Associated with myofibrillar myopathy 1.

**At a glance:** Uncertain significance · review: Multiple submitters · 2 submitters · 1 linked condition · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the DES gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 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.Ala273Pro |
| Coding change (HGVS c.) | c.817G>C |
| MANE Select transcript | [NM_001927](https://www.ncbi.nlm.nih.gov/nuccore/NM_001927) |
| Variant type | single nucleotide variant |
| Location | chr2:219420576-219420576 (GRCh38) |
| ClinVar | [VCV3501212](https://www.ncbi.nlm.nih.gov/clinvar/variation/3501212/) |

**All HGVS expressions:** `LRG_380:g.7200G>C`, `LRG_380t1:c.817G>C`, `NC_000002.11:g.220285298G>C`, `NC_000002.12:g.219420576G>C`, `NG_008043.1:g.7200G>C`, `NM_001382708.1:c.814G>C`, `NM_001382709.1:c.735+230G>C`, `NM_001382710.1:c.817G>C`, `NM_001382711.1:c.817G>C`, `NM_001382712.1:c.817G>C`, `NM_001382713.1:c.547G>C`, `NM_001927.4:c.817G>C`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.9991)
- REVEL 0.909 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -14.63 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- SpliceAI predicts **acceptor gain** (Δ 0.27) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 11.906, GERP 1.87, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 1%** most-pathogenic-predicted substitutions in DES (of 2,769 modeled).
- CADD: **PHRED 35.0**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.27**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.27**, donor gain **0.00**.
- 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 **273** lies in the if rod domain; the 'interaction with neb' region; the 'coil 2a' 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.Ala273Pro falls in the if rod domain.


### 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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-01-25.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2024–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-11-01 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-01-25 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Desmin-related myofibrillar myopathy, Cardiovascular phenotype, 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 **273** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [DES p.Ala273fs](/variant/des-p-ala273fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related DES variant pages (same residue, condition, or type): [DES p.Ala273Ser](/variant/des-p-ala273ser), [DES p.Ala273Thr](/variant/des-p-ala273thr), [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 2026-10-14); 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 3501212). 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.*