# NM_016938.5(EFEMP2):c.989C>G (p.Pro330Arg)

https://sugi.bio/variant/efemp2-p-pro330arg

## Summary

**EFEMP2 p.Pro330Arg (c.989C>G)** is classified **Uncertain significance** in EFEMP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-11-15). AlphaMissense: ambiguous (0.4712); Absent from gnomAD v4.1.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs781029572 · 1 submitter · AlphaMissense ambiguous · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the EFEMP2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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.*

**Support & next steps:** [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.Pro330Arg |
| Coding change (HGVS c.) | c.989C>G |
| MANE Select transcript | [NM_016938](https://www.ncbi.nlm.nih.gov/nuccore/NM_016938) |
| dbSNP | [rs781029572](https://www.ncbi.nlm.nih.gov/snp/rs781029572/) |
| Variant type | single nucleotide variant |
| Location | chr11:65868042-65868042 (GRCh38) |
| ClinVar | [VCV1310362](https://www.ncbi.nlm.nih.gov/clinvar/variation/1310362/) |

**All HGVS expressions:** `NC_000011.10:g.65868042G>C`, `NC_000011.9:g.65635513G>C`, `NG_012304.2:g.9893C>G`, `NG_053116.1:g.12981G>C`, `NM_016938.5:c.989C>G`, `NR_037718.2:n.1114C>G`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense makes no call; REVEL and SaProt both call this damaging; AlphaMissense makes no call — descriptive only.

- AlphaMissense **ambiguous** (0.4712) — no call either way
- REVEL 0.72 (pathogenic-leaning)
- SaProt LLR -10.658 (damaging)
- → **In-silico consensus:** REVEL and SaProt both call this damaging; AlphaMissense makes no call
- Conservation: phyloP 9.958, GERP 1.86, phastCons 1 — highly conserved
- CADD: **PHRED 31.0**. 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 (65,866,921–65,872,354), spanning 5,433 bp. Chi-square p 3.8e-05. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.82 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- 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}

**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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2019-11-15.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2019-11-15 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related EFEMP2 variant pages (same residue, condition, or type): [EFEMP2 p.Pro330Leu](/variant/efemp2-p-pro330leu), [EFEMP2 p.Pro330=](/variant/efemp2-p-pro330), [EFEMP2 p.Arg279Cys](/variant/efemp2-p-arg279cys), [EFEMP2 p.Arg337Ter](/variant/efemp2-p-arg337ter), [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).

### 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 1310362). 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.*