# NM_000094.4(COL7A1):c.4987C>A (p.Pro1663Thr)

https://sugi.bio/variant/col7a1-p-pro1663thr

## Summary

**COL7A1 p.Pro1663Thr (c.4987C>A)** is classified **Uncertain significance** in COL7A1 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2024-12-16). AlphaMissense: likely benign (0.0835); Ultra-rare (popmax 0.0318%, sas); Associated with recessive dystrophic epidermolysis bullosa.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs149342284 · 7 submitters · 7 linked conditions · AlphaMissense likely benign · ultra-rare (popmax 0.0318%, sas)

## For patients & families {#patients}

This is a change in the COL7A1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 7 submitters, 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.Pro1663Thr |
| Coding change (HGVS c.) | c.4987C>A |
| MANE Select transcript | [NM_000094](https://www.ncbi.nlm.nih.gov/nuccore/NM_000094) |
| dbSNP | [rs149342284](https://www.ncbi.nlm.nih.gov/snp/rs149342284/) |
| Variant type | single nucleotide variant |
| Location | chr3:48580646-48580646 (GRCh38) |
| ClinVar | [VCV991830](https://www.ncbi.nlm.nih.gov/clinvar/variation/991830/) |

**All HGVS expressions:** `LRG_286:g.19607C>A`, `NC_000003.11:g.48618079G>T`, `NC_000003.12:g.48580646G>T`, `NG_007065.1:g.19607C>A`, `NM_000094.3:c.4987C>A`, `NM_000094.4:c.4987C>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0835)
- REVEL 0.468 (indeterminate)
- Conservation: phyloP 7.389, GERP 2.05, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 24.3**. 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: **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 **0.0318%** (sas) · FAF95 0.026% · FAF99 0.0251% · 29/91,076 in the highest group · 379/1,613,642 alleles overall — ultra-rare (popmax 0.0318%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.0318% | 3,141 |
| European (non-Finnish) | 0.0286% | 3,501 |
| Middle Eastern | 0.0164% | 6,082 |
| Remaining individuals (not grpmax-eligible) | 0.008% | 12,494 |
| Finnish (not grpmax-eligible) | 0.00781% | 12,800 |
| Admixed American | 0.00167% | 59,964 |
| African / African-American | 0.00134% | 74,756 |

*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 **1663** lies in the 'disordered' region; the 'triple-helical 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.Pro1663Thr 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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-12-16.

**Submitter consensus:** unanimous (7/7 Uncertain significance).

**Submission history:** 7 submissions (2020–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Natera, Inc. | Uncertain significance | no assertion criteria provided | clinical testing | 2020-07-31 |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-01-06 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-01-11 |
| Breakthrough Genomics, Breakthrough Genomics | Uncertain significance | criteria provided, single submitter | not provided |  |
| PreventionGenetics, part of Exact Sciences | Uncertain significance | no assertion criteria provided | clinical testing | 2024-04-13 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-12-16 |
| Department of Pathology and Laboratory Medicine, Sinai Health System | Uncertain significance | criteria provided, single submitter | research | 2022-02-18 |

## Associated conditions {#conditions}

[recessive dystrophic epidermolysis bullosa](https://sugi.bio/atlas/disease/recessive-dystrophic-epidermolysis-bullosa/), [transient bullous dermolysis of the newborn](https://sugi.bio/atlas/disease/transient-bullous-dermolysis-of-the-newborn/), [generalized dominant dystrophic epidermolysis bullosa](https://sugi.bio/atlas/disease/generalized-dominant-dystrophic-epidermolysis-bullosa/), [pretibial dystrophic epidermolysis bullosa](https://sugi.bio/atlas/disease/pretibial-dystrophic-epidermolysis-bullosa/), [epidermolysis bullosa with congenital localized absence of skin and deformity of nails](https://sugi.bio/atlas/disease/epidermolysis-bullosa-with-congenital-localized-absence-of-skin-and-deformity-of-nails/), [dystrophic epidermolysis bullosa pruriginosa](https://sugi.bio/atlas/disease/dystrophic-epidermolysis-bullosa-pruriginosa/), [nonsyndromic congenital nail disorder 8](https://sugi.bio/atlas/disease/nonsyndromic-congenital-nail-disorder-8/).

**Reported phenotype names (ClinVar):** Recessive dystrophic epidermolysis bullosa, Epidermolysis bullosa dystrophica inversa, autosomal recessive, Dominant dystrophic epidermolysis bullosa with absence of skin, Epidermolysis bullosa pruriginosa, Generalized dominant dystrophic epidermolysis bullosa, Nonsyndromic congenital nail disorder 8, Pretibial dystrophic epidermolysis bullosa, Transient bullous dermolysis of the newborn, not specified, not provided.

## Similar variants {#similar}

Related COL7A1 variant pages (same residue, condition, or type): [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), [COL7A1 c.2993-2A>G](/variant/col7a1-c-2993-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 991830). 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.*