# NM_004006.3(DMD):c.79G>C (p.Ala27Pro)

https://sugi.bio/variant/dmd-p-ala27pro

## Summary

**DMD p.Ala27Pro (c.79G>C)** is classified **Conflicting classifications of pathogenicity** in DMD (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-10-21). AlphaMissense: likely pathogenic (0.9797); Absent from gnomAD v4.1; Associated with Cardiovascular phenotype.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs886043234 · 4 submitters · 2 linked conditions · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the DMD gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 4 submitters, and is linked to Cardiovascular phenotype.

*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.Ala27Pro |
| Coding change (HGVS c.) | c.79G>C |
| MANE Select transcript | [NM_004006](https://www.ncbi.nlm.nih.gov/nuccore/NM_004006) |
| dbSNP | [rs886043234](https://www.ncbi.nlm.nih.gov/snp/rs886043234/) |
| Variant type | single nucleotide variant |
| Location | chrX:33020153-33020153 (GRCh38) |
| ClinVar | [VCV285850](https://www.ncbi.nlm.nih.gov/clinvar/variation/285850/) |

**All HGVS expressions:** `LRG_199:g.324457G>C`, `LRG_199t1:c.79G>C`, `NC_000023.10:g.33038270C>G`, `NC_000023.11:g.33020153C>G`, `NG_012232.1:g.324457G>C`, `NM_000109.4:c.55G>C`, `NM_004006.2:c.79G>C`, `NM_004006.3:c.79G>C`, `NM_004009.3:c.67G>C`, `NM_004010.3:c.-291G>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9797)
- REVEL 0.744 (pathogenic-leaning) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and REVEL both call this damaging
- Conservation: phyloP 4.748, GERP 1.85, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 6%** most-pathogenic-predicted substitutions in DMD (of 21,669 modeled).
- CADD: **PHRED 24.4**. 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: **below the reporting threshold**. This position is scored for a different substitution (C>T, Δ0.31 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: **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}

**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 **27** lies in the calponin-homology (ch) 1 domain; an α-helix; the 'actin-binding' region.

**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. p.Ala27Pro falls in the calponin-homology (ch) 1 domain.


### 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-10-21.

**Submitter consensus:** conflicting (3 Uncertain significance, 1 Likely pathogenic).

**Submission history:** 4 submissions (2016–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Eurofins Ntd Llc (ga) | Uncertain significance | criteria provided, single submitter | clinical testing | 2016-01-21 |
| Revvity Omics, Revvity | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-11-30 |
| Ambry Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-10-21 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2020-12-20 |

## Associated conditions {#conditions}

[Cardiovascular phenotype](https://sugi.bio/atlas/disease/cardiovascular-phenotype/), [Duchenne muscular dystrophy](https://sugi.bio/atlas/disease/duchenne-muscular-dystrophy/).

**Reported phenotype names (ClinVar):** Cardiovascular phenotype, not provided, Duchenne muscular dystrophy, none provided, Duchenne Muscular Dystrophy (DMD), MUSCULAR DYSTROPHY, PSEUDOHYPERTROPHIC PROGRESSIVE, DUCHENNE TYPE.

## Same-residue context {#hotspot}

Residue **27** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [DMD p.Ala27fs](/variant/dmd-p-ala27fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related DMD variant pages (same residue, condition, or type): [DMD p.Ala27Glu](/variant/dmd-p-ala27glu), [DMD p.Ala27Val](/variant/dmd-p-ala27val), [DMD p.Ala27=](/variant/dmd-p-ala27), [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).

### 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 285850). 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.*