# NM_002204.4(ITGA3):c.240dup (p.Pro81fs)

https://sugi.bio/variant/itga3-p-pro81fs

## Summary

**ITGA3 p.Pro81fs (c.240dup)** is classified **Pathogenic/Likely pathogenic** in ITGA3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-12). Very rare (popmax 0.00133%, afr); Associated with epidermolysis bullosa, junctional 7, with interstitial lung disease and nephrotic syndrome.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs1416855722 · 2 submitters · 1 linked condition · very rare (popmax 0.00133%, afr)

## For patients & families {#patients}

This is a change in the ITGA3 gene that is considered likely disease-causing, submitted by 2 submitters, and is linked to epidermolysis bullosa, junctional 7, with interstitial lung disease and nephrotic syndrome.

*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) | Infancy, Neonatal |
| Diagnostic panels | ITGA3 is a diagnostic-grade gene on 10 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017377/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ITGA3](https://sugi.bio/atlas/gene/ITGA3/) |
| Protein change (HGVS p.) | p.Pro81fs |
| Coding change (HGVS c.) | c.240dup |
| MANE Select transcript | [NM_002204](https://www.ncbi.nlm.nih.gov/nuccore/NM_002204) |
| dbSNP | [rs1416855722](https://www.ncbi.nlm.nih.gov/snp/rs1416855722/) |
| Variant type | Duplication |
| Location | chr17:50064109-50064110 (GRCh38) |
| ClinVar | [VCV2127941](https://www.ncbi.nlm.nih.gov/clinvar/variation/2127941/) |

**All HGVS expressions:** `NC_000017.10:g.48141474dup`, `NC_000017.11:g.50064110dup`, `NG_029107.2:g.13135dup`, `NG_087081.1:g.103dup`, `NM_002204.4:c.240dup`

## 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 1.876, GERP 0.706, phastCons 0.025 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.69, pLI 2.2512e-10. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 2 of 26**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00133%** (afr) · 1/74,980 in the highest group · 1/1,612,770 alleles overall — very rare (popmax 0.00133%, afr).

*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}

**ITGA3** population constraint: LOEUF 0.69, pLI 2.2512e-10, missense-Z 2.7063. *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):

- **epidermolysis bullosa, junctional 7, with interstitial lung disease and nephrotic syndrome** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 83.88, 45% of residues very-high.

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

*Describes the biological roles of ITGA3 (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:** ITGA3's established molecular role includes protease binding.


### Pathways affected {#pathways}

ITGA3 participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Basigin interactions](https://reactome.org/content/detail/R-HSA-210991) | curated |
| [Laminin interactions](https://reactome.org/content/detail/R-HSA-3000157) | curated |
| [MET activates PTK2 signaling](https://reactome.org/content/detail/R-HSA-8874081) | curated |
| [Integrin cell surface interactions](https://reactome.org/content/detail/R-HSA-216083) | electronic |

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

**Molecular function:** protease binding, protein heterodimerization activity.

**Biological process:** regulation of transforming growth factor beta receptor signaling pathway, regulation of Wnt signaling pathway, lung development, regulation of BMP signaling pathway, skin development, mesodermal cell differentiation.

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-06-12.

**Submitter consensus:** conflicting (1 Likely pathogenic, 1 Pathogenic).

**Submission history:** 2 submissions (2024–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Fulgent Genetics, Fulgent Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-02-08 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-06-12 |

## Associated conditions {#conditions}

[epidermolysis bullosa, junctional 7, with interstitial lung disease and nephrotic syndrome](https://sugi.bio/atlas/disease/epidermolysis-bullosa-junctional-7-with-interstitial-lung-disease-and-nephrotic-syndrome/).

**Reported phenotype names (ClinVar):** Epidermolysis bullosa, junctional 7, with interstitial lung disease and nephrotic syndrome, not provided, none provided, Interstitial lung disease, nephrotic syndrome, and epidermolysis bullosa, congenital, Interstitial Lung Disease with Nephrotic Syndrome and Epidermolysis Bullosa.

## Similar variants {#similar}

Related ITGA3 variant pages (same residue, condition, or type): [ITGA3 p.Ala896fs](/variant/itga3-p-ala896fs), [ITGA3 p.Val756fs](/variant/itga3-p-val756fs), [ITGA3 c.2920-6_2920-1dup](/variant/itga3-c-2920-minus-6-2920-minus-1dup), [ITGA3 p.Pro81=](/variant/itga3-p-pro81), [ITGA3 c.2070+1G>A](/variant/itga3-c-2070-plus-1g-a), [ITGA3 p.Arg274Gln](/variant/itga3-p-arg274gln), [ITGA3 p.Arg875Ter](/variant/itga3-p-arg875ter), [ITGA3 c.*48G>A](/variant/itga3-c-star-48g-a).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 2127941). 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.*