# NM_004006.3(DMD):c.6571C>T (p.Arg2191Trp)

https://sugi.bio/variant/dmd-p-arg2191trp

## Summary

**DMD p.Arg2191Trp (c.6571C>T)** is classified **Benign/Likely benign** in DMD (ClinVar, Multiple submitters, 18 submitters; last evaluated 2026-01-31). AlphaMissense: likely benign (0.2979); Ultra-rare (popmax 0.0548%, amr); Associated with Duchenne or Becker muscular dystrophy.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs149322279 · 18 submitters · 4 linked conditions · AlphaMissense likely benign · ultra-rare (popmax 0.0548%, amr)

## For patients & families {#patients}

This is a change in the DMD gene that is classified as benign/likely benign — not considered disease-causing, submitted by 18 submitters, and is linked to Duchenne or 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.*

**Support & next steps:** [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.Arg2191Trp |
| Coding change (HGVS c.) | c.6571C>T |
| MANE Select transcript | [NM_004006](https://www.ncbi.nlm.nih.gov/nuccore/NM_004006) |
| dbSNP | [rs149322279](https://www.ncbi.nlm.nih.gov/snp/rs149322279/) |
| Variant type | single nucleotide variant |
| Location | chrX:31968382-31968382 (GRCh38) |
| ClinVar | [VCV197522](https://www.ncbi.nlm.nih.gov/clinvar/variation/197522/) |

**All HGVS expressions:** `LRG_199:g.1376228C>T`, `LRG_199t1:c.6571C>T`, `NC_000023.10:g.31986499G>A`, `NC_000023.11:g.31968382G>A`, `NG_012232.1:g.1376228C>T`, `NM_000109.4:c.6547C>T`, `NM_004006.3:c.6571C>T`, `NM_004009.3:c.6559C>T`, `NM_004010.3:c.6202C>T`, `NM_004011.4:c.2548C>T`, `NM_004012.4:c.2539C>T`, `NM_004013.3:c.-810C>T`, `NM_004020.4:c.-810C>T`, `NM_004021.3:c.-810C>T`, `NM_004022.3:c.-810C>T`, `NM_004023.3:c.-810C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.2979)
- REVEL 0.403 (indeterminate)
- Conservation: phyloP 8.495, GERP 1.55, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 25.7**. 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 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: **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 **0.0548%** (amr) · FAF95 0.0381% · FAF99 0.0325% · 25/45,594 in the highest group · 270/1,208,397 alleles overall — ultra-rare (popmax 0.0548%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Ashkenazi Jewish (not grpmax-eligible) | 0.246% | 407 |
| Admixed American (grpmax) | 0.0548% | 1,824 |
| Middle Eastern | 0.0458% | 2,184 |
| Remaining individuals (not grpmax-eligible) | 0.04% | 2,502 |
| South Asian | 0.0264% | 3,785 |
| European (non-Finnish) | 0.0171% | 5,846 |
| East Asian | 0.00297% | 33,713 |
| African / African-American | 0.00176% | 56,891 |

Ashkenazi Jewish 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}

**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 **2191** lies in a UniProt-annotated variant site (in).

**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}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-31.

**Submitter consensus:** conflicting (10 Likely benign, 7 Benign, 1 Likely Benign).

**Submission history:** 18 submissions (2015–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genetic Services Laboratory, University of Chicago | Likely benign | criteria provided, single submitter | clinical testing | 2016-11-22 |
| Athena Diagnostics | Benign | criteria provided, single submitter | clinical testing | 2016-09-27 |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Likely benign | criteria provided, single submitter | clinical testing | 2018-06-29 |
| Natera, Inc. | Likely benign | no assertion criteria provided | clinical testing | 2019-06-21 |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2020-01-06 |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Likely Benign | criteria provided, single submitter | clinical testing | 2024-03-26 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-01-31 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2024-06-01 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Benign | criteria provided, single submitter | clinical testing | 2019-06-03 |
| Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | Likely benign | no assertion criteria provided | clinical testing |  |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2019-04-04 |
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Likely benign | no assertion criteria provided | clinical testing |  |
| Ambry Genetics | Benign | criteria provided, single submitter | clinical testing | 2017-06-28 |
| Eurofins Ntd Llc (ga) | Benign | criteria provided, single submitter | clinical testing | 2015-04-13 |
| Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | Likely benign | criteria provided, single submitter | clinical testing | 2025-04-08 |
| Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service | Likely benign | criteria provided, single submitter | clinical testing | 2025-05-07 |
| Stanford Center for Inherited Cardiovascular Disease, Stanford University | Likely benign | criteria provided, single submitter | provider interpretation | 2017-11-08 |
| Blueprint Genetics | Benign | criteria provided, single submitter | clinical testing | 2024-10-30 |

## Associated conditions {#conditions}

[Duchenne or Becker muscular dystrophy](https://sugi.bio/atlas/disease/duchenne-or-becker-muscular-dystrophy/), [cardiomyopathy](https://sugi.bio/atlas/disease/cardiomyopathy/), [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):** Duchenne or Becker muscular dystrophy, not specified, Cardiovascular phenotype, not provided, Duchenne muscular dystrophy, Becker muscular dystrophy, Cardiomyopathy, Dystrophin deficiency, DMD-related disorder, Becker Muscular Dystrophy (BMD).

## Similar variants {#similar}

Related DMD variant pages (same residue, condition, or type): [DMD p.Arg2191Gln](/variant/dmd-p-arg2191gln), [DMD p.Arg2191=](/variant/dmd-p-arg2191), [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).

### 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 197522). 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.*