# NM_000094.4(COL7A1):c.3977G>T (p.Gly1326Val)

https://sugi.bio/variant/col7a1-p-gly1326val

## Summary

**COL7A1 p.Gly1326Val (c.3977G>T)** is classified **Likely pathogenic** in COL7A1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-19). AlphaMissense: likely pathogenic (0.5829); Absent from gnomAD v4.1; Associated with recessive dystrophic epidermolysis bullosa.

**At a glance:** Likely pathogenic · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the COL7A1 gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to recessive dystrophic epidermolysis bullosa.

*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 recessive |
| Age of onset (of this condition) | Neonatal |
| Prevalence | 1-9 / 1 000 000 (United States) |
| Clinical trials | 30 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | COL7A1 is a diagnostic-grade gene on 3 Genomics England panels |

**Commonly reported features of Autosomal recessive generalized dystrophic epidermolysis bullosa, severe form** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Carious teeth — Very frequent (99-80%)
- Fragile skin — Very frequent (99-80%)
- Milia — Very frequent (99-80%)
- Atrophic scars — Very frequent (99-80%)
- Flexion contracture — Very frequent (99-80%)
- Growth delay — Very frequent (99-80%)
- Anemia — Very frequent (99-80%)
- Mitten deformity — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0006308/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [COL7A1](https://sugi.bio/atlas/gene/COL7A1/) |
| Protein change (HGVS p.) | p.Gly1326Val |
| Coding change (HGVS c.) | c.3977G>T |
| MANE Select transcript | [NM_000094](https://www.ncbi.nlm.nih.gov/nuccore/NM_000094) |
| Variant type | single nucleotide variant |
| Location | chr3:48584944-48584944 (GRCh38) |
| ClinVar | [VCV3393058](https://www.ncbi.nlm.nih.gov/clinvar/variation/3393058/) |

**All HGVS expressions:** `LRG_286:g.15309G>T`, `LRG_286t1:c.3977G>T`, `NC_000003.11:g.48622377C>A`, `NC_000003.12:g.48584944C>A`, `NG_007065.1:g.15309G>T`, `NM_000094.4:c.3977G>T`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.5829) — concordant with the pathogenic call
- REVEL 0.869 (moderately pathogenic-leaning) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and REVEL both call this damaging
- SpliceAI predicts **acceptor gain** (Δ 0.20) — consistent with the pathogenic call
- Conservation: phyloP 7.561, GERP 1.79, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 25.2**. 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 0.83** across the covering region of the MANE Select transcript (48,564,409–48,586,597), spanning 22,188 bp. Chi-square p 7.2e-17. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.20**, donor gain **0.19**. Largest is acceptor gain, 1 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.19**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- 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}

**COL7A1** population constraint: LOEUF 0.69, pLI 1.4204e-56, missense-Z 4.0644. *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):

- **recessive dystrophic epidermolysis bullosa** — Definitive (AR)

## Protein context {#protein}

Residue **1326** lies in the 'disordered' region; the 'triple-helical region' region; the 'interrupted collagenous region' region.

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

*Describes the biological roles of COL7A1 (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:** COL7A1's established molecular role includes extracellular matrix structural constituent conferring tensile strength. p.Gly1326Val falls in the disordered region.


### Pathways affected {#pathways}

COL7A1 participates in **10 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Anchoring fibril formation](https://reactome.org/content/detail/R-HSA-2214320) | curated |
| [Assembly of collagen fibrils and other multimeric structures](https://reactome.org/content/detail/R-HSA-2022090) | curated |
| [COPII-mediated vesicle transport](https://reactome.org/content/detail/R-HSA-204005) | curated |
| [Cargo concentration in the ER](https://reactome.org/content/detail/R-HSA-5694530) | curated |
| [Collagen biosynthesis and modifying enzymes](https://reactome.org/content/detail/R-HSA-1650814) | curated |
| [Collagen chain trimerization](https://reactome.org/content/detail/R-HSA-8948216) | curated |
| [Fibronectin matrix formation](https://reactome.org/content/detail/R-HSA-1566977) | curated |
| [Integrin cell surface interactions](https://reactome.org/content/detail/R-HSA-216083) | curated |
| [Collagen degradation](https://reactome.org/content/detail/R-HSA-1442490) | electronic |
| [Laminin interactions](https://reactome.org/content/detail/R-HSA-3000157) | electronic |

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

**Molecular function:** extracellular matrix structural constituent conferring tensile strength.

**Biological process:** endodermal cell differentiation.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-12-19.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-12-19 |

## Associated conditions {#conditions}

[recessive dystrophic epidermolysis bullosa](https://sugi.bio/atlas/disease/recessive-dystrophic-epidermolysis-bullosa/).

**Reported phenotype names (ClinVar):** Recessive dystrophic epidermolysis bullosa, DYSTROPHIC EPIDERMOLYSIS BULLOSA, AUTOSOMAL RECESSIVE, EPIDERMOLYSIS BULLOSA DYSTROPHICA, HALLOPEAU-SIEMENS TYPE, Hallopeau-Siemens Disease, EPIDERMOLYSIS BULLOSA DYSTROPHICA, GENERALIZED SEVERE, AUTOSOMAL RECESSIVE, epidermolysis bullosa dystrophica, autosomal recessive, Recessive DEB (RDEB), severe generalized recessive dystrophic epidermolysis bullosa, Epidermolysis Bullosa Distrophica Autosomal Recessive (RDEB).

## Similar variants {#similar}

Related COL7A1 variant pages (same residue, condition, or type): [COL7A1 p.Gly1326=](/variant/col7a1-p-gly1326), [COL7A1 c.1240+1G>T](/variant/col7a1-c-1240-plus-1g-t), [COL7A1 c.1637-1G>A](/variant/col7a1-c-1637-minus-1g-a), [COL7A1 c.1906+1G>T](/variant/col7a1-c-1906-plus-1g-t), [COL7A1 c.2171-2A>G](/variant/col7a1-c-2171-minus-2a-g), [COL7A1 c.2587+1G>A](/variant/col7a1-c-2587-plus-1g-a), [COL7A1 c.266+1G>A](/variant/col7a1-c-266-plus-1g-a), [COL7A1 c.266+2T>C](/variant/col7a1-c-266-plus-2t-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 3393058). 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.*