# NM_001927.4(DES):c.212C>T (p.Ala71Val)

https://sugi.bio/variant/des-p-ala71val

## Summary

**DES p.Ala71Val (c.212C>T)** is classified **Uncertain significance** in DES (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-08). AlphaMissense: likely benign (0.0941); Very rare (popmax 0.000602%, nfe); Associated with myofibrillar myopathy 1.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs759235186 · 2 submitters · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.000602%, nfe)

## 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.Ala71Val |
| Coding change (HGVS c.) | c.212C>T |
| MANE Select transcript | [NM_001927](https://www.ncbi.nlm.nih.gov/nuccore/NM_001927) |
| dbSNP | [rs759235186](https://www.ncbi.nlm.nih.gov/snp/rs759235186/) |
| Variant type | single nucleotide variant |
| Location | chr2:219418674-219418674 (GRCh38) |
| ClinVar | [VCV222541](https://www.ncbi.nlm.nih.gov/clinvar/variation/222541/) |

**All HGVS expressions:** `LRG_380:g.5298C>T`, `LRG_380t1:c.212C>T`, `NC_000002.11:g.220283396C>T`, `NC_000002.12:g.219418674C>T`, `NG_008043.1:g.5298C>T`, `NM_001927.4:c.212C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0941)
- REVEL 0.196 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -7.206 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 3.947, GERP -0.512, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 21.7**. 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 **0.000602%** (nfe) · FAF95 0.00025% · FAF99 0.000161% · 7/1,163,262 in the highest group · 8/1,427,684 alleles overall — very rare (popmax 0.000602%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.00163% | 61,180 |
| European (non-Finnish) (grpmax) | 0.000602% | 166,180 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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 **71** lies in 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.Ala71Val 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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-11-08.

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

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-02-29 |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-11-08 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Desmin-related myofibrillar myopathy, not provided, Desminopathy, Myofibrillar myopathy 1, MYOFIBRILLAR MYOPATHY WITH ARRHYTHMOGENIC RIGHT VENTRICULAR CARDIOMYOPATHY, DESMIN-RELATED MYOPATHY WITH ARRHYTHMOGENIC RIGHT VENTRICULAR CARDIOMYOPATHY, Desmin related myopathy (former name), Desmin storage myopathy (former name), none provided.

## Similar variants {#similar}

Related DES variant pages (same residue, condition, or type): [DES p.Ala71Gly](/variant/des-p-ala71gly), [DES p.Ala71Ser](/variant/des-p-ala71ser), [DES p.Ala71=](/variant/des-p-ala71), [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).

### 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 222541). 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.*