# NM_004006.3(DMD):c.1351G>T (p.Asp451Tyr)

https://sugi.bio/variant/dmd-p-asp451tyr

## Summary

**DMD p.Asp451Tyr (c.1351G>T)** is classified **Pathogenic/Likely pathogenic** in DMD (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-09-01). AlphaMissense: likely benign (0.1503); No allele count reported in gnomAD v4.1 (AN 1,206,817); Associated with Becker muscular dystrophy.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs1602169535 · 3 submitters · 2 linked conditions · AlphaMissense likely benign · no allele count reported in gnomAD v4.1 (AN 1,206,817)

## For patients & families {#patients}

This is a change in the DMD gene that is considered likely disease-causing, submitted by 3 submitters, and is linked to Becker muscular dystrophy.

*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) | X-linked recessive |
| Age of onset (of this condition) | Adolescent, Adult, Childhood, Elderly |
| Prevalence | 1-9 / 100 000 (Europe) |
| Clinical trials | 74 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | DMD is a diagnostic-grade gene on 17 Genomics England panels |

**Commonly reported features of Becker muscular dystrophy** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Gait disturbance — Very frequent (99-80%)
- Myoglobinuria — Very frequent (99-80%)
- Elevated circulating creatine kinase concentration — Very frequent (99-80%)
- Myalgia — Very frequent (99-80%)
- Exercise intolerance — Very frequent (99-80%)
- Difficulty climbing stairs — Very frequent (99-80%)
- Abnormal urinary color — Very frequent (99-80%)
- Muscle weakness — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0005900/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DMD](https://sugi.bio/atlas/gene/DMD/) |
| Protein change (HGVS p.) | p.Asp451Tyr |
| Coding change (HGVS c.) | c.1351G>T |
| MANE Select transcript | [NM_004006](https://www.ncbi.nlm.nih.gov/nuccore/NM_004006) |
| dbSNP | [rs1602169535](https://www.ncbi.nlm.nih.gov/snp/rs1602169535/) |
| Variant type | single nucleotide variant |
| Location | chrX:32614434-32614434 (GRCh38) |
| ClinVar | [VCV642449](https://www.ncbi.nlm.nih.gov/clinvar/variation/642449/) |

**All HGVS expressions:** `LRG_199:g.730176G>T`, `LRG_199t1:c.1351G>T`, `NC_000023.10:g.32632551C>A`, `NC_000023.11:g.32614434C>A`, `NG_012232.1:g.730176G>T`, `NM_000109.4:c.1327G>T`, `NM_004006.3:c.1351G>T`, `NM_004009.3:c.1339G>T`, `NM_004010.3:c.982G>T`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — AlphaMissense predicts likely-benign.

- AlphaMissense **likely benign** (0.1503) — ⚠ discordant with the pathogenic call
- REVEL 0.302 (indeterminate)
- SpliceAI predicts **acceptor gain** (Δ 0.87) — consistent with the pathogenic call
- Conservation: phyloP 4.873, GERP 1.5, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 34.0**. 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 1.36** across the covering region of the MANE Select transcript (31,348,585–33,211,312), spanning 1,862,727 bp. Chi-square p 2.4e-62. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.41**, donor loss **0.00**, acceptor gain **0.87**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.41**, donor loss **0.00**, acceptor gain **0.87**, donor gain **0.00**.
- Pangolin: Δ**0.77** (gain), gain 0.77 / loss 0.70. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency: **no allele count reported in gnomAD v4.1 (AN 1,206,817)** — 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}

**DMD** population constraint: ClinGen dosage — haploinsufficiency 3, triplosensitivity 0 (0–3 scale). *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):

- **progressive muscular dystrophy** — Definitive (XL)

## Protein context {#protein}

Residue **451** lies in an α-helix.

**6 experimental structure(s)** (PDB): [1DXX](https://www.rcsb.org/structure/1DXX), [1EG3](https://www.rcsb.org/structure/1EG3), [1EG4](https://www.rcsb.org/structure/1EG4), [3UUN](https://www.rcsb.org/structure/3UUN), [9D58](https://www.rcsb.org/structure/9D58), [9EC1](https://www.rcsb.org/structure/9EC1).

## What this gene does {#gene-function}

*Describes the biological roles of DMD (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:** DMD's established molecular role includes dystroglycan binding.


### Pathways affected {#pathways}

DMD participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Striated Muscle Contraction](https://reactome.org/content/detail/R-HSA-390522) | curated |
| [Formation of the dystrophin-glycoprotein complex (DGC)](https://reactome.org/content/detail/R-HSA-9913351) | electronic |
| [Non-integrin membrane-ECM interactions](https://reactome.org/content/detail/R-HSA-3000171) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** dystroglycan binding, actin binding, structural constituent of muscle, myosin binding, vinculin binding.

**Biological process:** regulation of heart rate, intracellular protein localization, positive regulation of neuron projection development, peptide biosynthetic process, positive regulation of neuron differentiation, cardiac muscle contraction.

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-09-01.

**Submitter consensus:** conflicting (2 Pathogenic, 1 Likely pathogenic).

**Submission history:** 3 submissions (2022–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| 3billion | Likely pathogenic | criteria provided, single submitter | clinical testing | 2022-03-22 |
| Mendelics | Pathogenic | criteria provided, single submitter | clinical testing | 2022-05-04 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-09-01 |

## Associated conditions {#conditions}

[Becker muscular dystrophy](https://sugi.bio/atlas/disease/becker-muscular-dystrophy/), [Duchenne muscular dystrophy](https://sugi.bio/atlas/disease/duchenne-muscular-dystrophy/).

**Reported phenotype names (ClinVar):** Becker muscular dystrophy, Duchenne muscular dystrophy, MUSCULAR DYSTROPHY, PSEUDOHYPERTROPHIC PROGRESSIVE, BECKER TYPE, Becker Muscular Dystrophy (BMD), MUSCULAR DYSTROPHY, PSEUDOHYPERTROPHIC PROGRESSIVE, DUCHENNE TYPE, Duchenne Muscular Dystrophy (DMD).

## Similar variants {#similar}

Related DMD variant pages (same residue, condition, or type): [DMD c.10086+1G>A](/variant/dmd-c-10086-plus-1g-a), [DMD c.10086+1G>T](/variant/dmd-c-10086-plus-1g-t), [DMD c.10086+2T>C](/variant/dmd-c-10086-plus-2t-c), [DMD c.10087-2A>G](/variant/dmd-c-10087-minus-2a-g), [DMD c.10223+1G>A](/variant/dmd-c-10223-plus-1g-a), [DMD c.10223+1G>C](/variant/dmd-c-10223-plus-1g-c), [DMD c.10224-2A>G](/variant/dmd-c-10224-minus-2a-g), [DMD c.10554-2A>G](/variant/dmd-c-10554-minus-2a-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 642449). 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.*