# NM_004006.3(DMD):c.1464C>T (p.Arg488=)

https://sugi.bio/variant/dmd-p-arg488

## Summary

**DMD p.Arg488= (c.1464C>T)** is classified **Likely benign** in DMD (ClinVar, Single submitter, 3 submitters; last evaluated 2026-01-14). Ultra-rare (popmax 0.0179%, eas); Associated with Duchenne muscular dystrophy.

**At a glance:** Likely benign · review: Single submitter · rsID rs771891715 · 3 submitters · 3 linked conditions · ultra-rare (popmax 0.0179%, eas)

## For patients & families {#patients}

This is a change in the DMD gene that is classified as likely benign — not considered disease-causing, submitted by 3 submitters, and is linked to Duchenne 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) | Childhood |
| Prevalence | 1-9 / 100 000 (Worldwide) |
| Clinical trials | 373 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | DMD is a diagnostic-grade gene on 17 Genomics England panels |

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

- Delayed speech and language development — Very frequent (99-80%)
- Global developmental delay — Very frequent (99-80%)
- Motor delay — Very frequent (99-80%)
- Specific learning disability — Very frequent (99-80%)
- Flexion contracture — Very frequent (99-80%)
- Cardiomyopathy — Very frequent (99-80%)
- Respiratory insufficiency — Very frequent (99-80%)
- Waddling gait — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0006291/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.Arg488= |
| Coding change (HGVS c.) | c.1464C>T |
| MANE Select transcript | [NM_004006](https://www.ncbi.nlm.nih.gov/nuccore/NM_004006) |
| dbSNP | [rs771891715](https://www.ncbi.nlm.nih.gov/snp/rs771891715/) |
| Variant type | single nucleotide variant |
| Location | chrX:32614321-32614321 (GRCh38) |
| ClinVar | [VCV1114758](https://www.ncbi.nlm.nih.gov/clinvar/variation/1114758/) |

**All HGVS expressions:** `LRG_199:g.730289C>T`, `NC_000023.10:g.32632438G>A`, `NC_000023.11:g.32614321G>A`, `NG_012232.1:g.730289C>T`, `NM_000109.4:c.1440C>T`, `NM_004006.2:c.1464C>T`, `NM_004006.3:c.1464C>T`, `NM_004009.3:c.1452C>T`, `NM_004010.3:c.1095C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 2.092, GERP -0.188, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 7.568**. 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.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>C, Δ0.21 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0179%** (eas) · FAF95 0.00769% · FAF99 0.00529% · 6/33,591 in the highest group · 8/1,205,779 alleles overall — ultra-rare (popmax 0.0179%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.0179% | 5,599 |
| Admixed American | 0.00221% | 45,329 |
| Remaining individuals (not grpmax-eligible) | 0.00211% | 47,447 |

*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 3/3, triplosensitivity 0/3. *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}


**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}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2026-01-14.

**Submitter consensus:** unanimous (3/3 Likely benign).

**Submission history:** 3 submissions (2019–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Natera, Inc. | Likely benign | no assertion criteria provided | clinical testing | 2021-07-21 |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2019-11-12 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-14 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Duchenne muscular dystrophy, Becker muscular dystrophy, Cardiomyopathy, Dystrophin deficiency, DMD-related disorder, DMD-related condition, MUSCULAR DYSTROPHY, PSEUDOHYPERTROPHIC PROGRESSIVE, BECKER TYPE, Becker Muscular Dystrophy (BMD), Duchenne Muscular Dystrophy (DMD), MUSCULAR DYSTROPHY, PSEUDOHYPERTROPHIC PROGRESSIVE, DUCHENNE TYPE.

## Similar variants {#similar}

Related DMD variant pages (same residue, condition, or type): [DMD p.Arg488Cys](/variant/dmd-p-arg488cys), [DMD p.Arg488His](/variant/dmd-p-arg488his), [DMD p.Arg488Leu](/variant/dmd-p-arg488leu), [DMD p.Arg488Ser](/variant/dmd-p-arg488ser), [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).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2026-10-14); 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 1114758). 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.*