# NM_016938.5(EFEMP2):c.1070_1073dup (p.Asp359fs)

https://sugi.bio/variant/efemp2-p-asp359fs

## Summary

**EFEMP2 p.Asp359fs (c.1070_1073dup)** is classified **Pathogenic** in EFEMP2 (ClinVar, No assertion criteria, 2 submitters; last evaluated 2007-11-15). No gnomAD frequency available for this variant; Associated with cutis laxa, autosomal recessive, type 1B.

**At a glance:** Pathogenic · review: No assertion criteria · rsID rs193302865 · 2 submitters · 2 linked conditions · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the EFEMP2 gene that is reported as disease-causing, but on limited review, submitted by 2 submitters, and is linked to cutis laxa, autosomal recessive, type 1B.

*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 | EFEMP2 is a diagnostic-grade gene on 6 Genomics England panels |

**Commonly reported features of Autosomal recessive cutis laxa type 1** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Cutis laxa — Obligate (100%)
- Redundant skin — Very frequent (99-80%)
- Emphysema — Very frequent (99-80%)
- Dermatochalasis — Very frequent (99-80%)
- Fragmented elastic fibers in the dermis — Very frequent (99-80%)
- Lack of skin elasticity — Very frequent (99-80%)
- Joint hypermobility — Frequent (79-30%)
- Inguinal hernia — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015804/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [EFEMP2](https://sugi.bio/atlas/gene/EFEMP2/) |
| Protein change (HGVS p.) | p.Asp359fs |
| Coding change (HGVS c.) | c.1070_1073dup |
| MANE Select transcript | [NM_016938](https://www.ncbi.nlm.nih.gov/nuccore/NM_016938) |
| dbSNP | [rs193302865](https://www.ncbi.nlm.nih.gov/snp/rs193302865/) |
| Variant type | Duplication |
| Location | chr11:65867957-65867958 (GRCh38) |
| ClinVar | [VCV5425](https://www.ncbi.nlm.nih.gov/clinvar/variation/5425/) |

**All HGVS expressions:** `NC_000011.10:g.65867960_65867963dup`, `NC_000011.9:g.65635431_65635434dup`, `NG_012304.2:g.9974_9977dup`, `NG_053116.1:g.12899_12902dup`, `NM_016938.5:c.1070_1073dup`, `NR_037718.2:n.1195_1198dup`

## 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 -15.955, GERP -3.72 — fast-evolving / accelerated position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.56, pLI 0.62375. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 10 of 11**, 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: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**EFEMP2** population constraint: LOEUF 0.56, pLI 0.62375, missense-Z 1.7076. *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):

- **cutis laxa, autosomal recessive, type 1B** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 82.95, 55% of residues very-high.

**1 experimental structure(s)** (PDB): [2KL7](https://www.rcsb.org/structure/2KL7).

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

*Describes the biological roles of EFEMP2 (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:** EFEMP2's established molecular role includes heparin binding.


### Pathways affected {#pathways}

EFEMP2 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Molecules associated with elastic fibres](https://reactome.org/content/detail/R-HSA-2129379) | electronic |

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

**Molecular function:** heparin binding, protein homodimerization activity.

**Biological process:** elastic fiber assembly, positive regulation of smooth muscle cell-matrix adhesion.

## Clinical significance {#significance}

**Pathogenic** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2007-11-15.

**Submitter consensus:** conflicting (1 not provided, 1 Pathogenic).

**Submission history:** 2 submissions (2007); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneReviews | not provided | no classification provided | literature only |  |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2007-11-15 |

## Associated conditions {#conditions}

[cutis laxa, autosomal recessive, type 1B](https://sugi.bio/atlas/disease/cutis-laxa-autosomal-recessive-type-1b/), [cutis laxa, autosomal recessive, type 1A](https://sugi.bio/atlas/disease/cutis-laxa-autosomal-recessive-type-1a/).

**Reported phenotype names (ClinVar):** Cutis laxa, autosomal recessive, type 1B, Cutis laxa, autosomal recessive, type 1A, CUTIS LAXA, AUTOSOMAL RECESSIVE, TYPE IB, EFEMP2-Related Cutis Laxa, Autosomal recessive cutis laxa type IA.

## Similar variants {#similar}

Related EFEMP2 variant pages (same residue, condition, or type): [EFEMP2 p.Asp359=](/variant/efemp2-p-asp359), [EFEMP2 p.Cys287fs](/variant/efemp2-p-cys287fs), [EFEMP2 p.Arg354fs](/variant/efemp2-p-arg354fs), [EFEMP2 p.Glu324Ter](/variant/efemp2-p-glu324ter), [EFEMP2 p.Gly371fs](/variant/efemp2-p-gly371fs), [EFEMP2 p.Pro318fs](/variant/efemp2-p-pro318fs), [EFEMP2 p.Pro98fs](/variant/efemp2-p-pro98fs), [EFEMP2 p.Tyr307fs](/variant/efemp2-p-tyr307fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 5425). 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.*