# NM_016938.5(EFEMP2):c.204A>G (p.Glu68=)

https://sugi.bio/variant/efemp2-p-glu68

## Summary

**EFEMP2 p.Glu68= (c.204A>G)** is classified **Likely benign** in EFEMP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-19). Very rare (popmax 0.00534%, afr); Associated with cutis laxa, autosomal recessive, type 1B.

**At a glance:** Likely benign · review: Single submitter · rsID rs758569402 · 1 submitter · 1 linked condition · very rare (popmax 0.00534%, afr)

## For patients & families {#patients}

This is a change in the EFEMP2 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, 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.Glu68= |
| Coding change (HGVS c.) | c.204A>G |
| MANE Select transcript | [NM_016938](https://www.ncbi.nlm.nih.gov/nuccore/NM_016938) |
| dbSNP | [rs758569402](https://www.ncbi.nlm.nih.gov/snp/rs758569402/) |
| Variant type | single nucleotide variant |
| Location | chr11:65871320-65871320 (GRCh38) |
| ClinVar | [VCV2897761](https://www.ncbi.nlm.nih.gov/clinvar/variation/2897761/) |

**All HGVS expressions:** `NC_000011.10:g.65871320T>C`, `NC_000011.9:g.65638791T>C`, `NG_012304.2:g.6615A>G`, `NM_016938.5:c.204A>G`, `NR_037718.2:n.329A>G`

## 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 -0.483, GERP -3.72, phastCons 0.097 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 6.17**. 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.*
- 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 **0.00534%** (afr) · FAF95 0.00175% · FAF99 0.00104% · 4/74,916 in the highest group · 4/1,614,020 alleles overall — very rare (popmax 0.00534%, 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}

**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}

Residue **68** lies in the egf-like 1; atypical domain; a β-strand.

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. p.Glu68= falls in the egf-like 1; atypical domain.


### 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}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-12-19.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-12-19 |

## Associated conditions {#conditions}

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

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

## Similar variants {#similar}

Related EFEMP2 variant pages (same residue, condition, or type): [EFEMP2 p.Glu68Ala](/variant/efemp2-p-glu68ala), [EFEMP2 p.Arg279Cys](/variant/efemp2-p-arg279cys), [EFEMP2 p.Asp203Ala](/variant/efemp2-p-asp203ala), [EFEMP2 p.Glu126Lys](/variant/efemp2-p-glu126lys), [EFEMP2 p.Glu161Lys](/variant/efemp2-p-glu161lys), [EFEMP2 p.Glu167Ter](/variant/efemp2-p-glu167ter), [EFEMP2 c.161-6C>G](/variant/efemp2-c-161-minus-6c-g), [EFEMP2 c.491-5C>G](/variant/efemp2-c-491-minus-5c-g).

### 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 2026-10-14); 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 2897761). 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.*