# NM_016938.5(EFEMP2):c.964G>T (p.Val322Phe)

https://sugi.bio/variant/efemp2-p-val322phe

## Summary

**EFEMP2 p.Val322Phe (c.964G>T)** is classified **Uncertain significance** in EFEMP2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-09-17). AlphaMissense: likely benign (0.3135); Very rare (popmax 8.47e-05%, nfe); Associated with Cardiovascular phenotype.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs759573856 · 2 submitters · 2 linked conditions · AlphaMissense likely benign · very rare (popmax 8.47e-05%, nfe)

## 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 2 submitters, and is linked to Cardiovascular phenotype.

*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.Val322Phe |
| Coding change (HGVS c.) | c.964G>T |
| MANE Select transcript | [NM_016938](https://www.ncbi.nlm.nih.gov/nuccore/NM_016938) |
| dbSNP | [rs759573856](https://www.ncbi.nlm.nih.gov/snp/rs759573856/) |
| Variant type | single nucleotide variant |
| Location | chr11:65868305-65868305 (GRCh38) |
| ClinVar | [VCV1381687](https://www.ncbi.nlm.nih.gov/clinvar/variation/1381687/) |

**All HGVS expressions:** `NC_000011.10:g.65868305C>A`, `NC_000011.9:g.65635776C>A`, `NG_012304.2:g.9630G>T`, `NG_053116.1:g.13244C>A`, `NM_016938.5:c.964G>T`, `NR_037718.2:n.1089G>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.3135)
- REVEL 0.668 (pathogenic-leaning) — differs from AlphaMissense
- SaProt LLR -8.179 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** REVEL calls this damaging; AlphaMissense and SaProt do not
- SpliceAI predicts **donor loss** (Δ 0.29) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 3.352, GERP -1.84, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 26.1**. 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 deltas (raw): acceptor loss **0.01**, donor loss **0.29**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss, 1 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **8.47e-05%** (nfe) · 1/1,180,026 in the highest group · 1/1,613,730 alleles overall — very rare (popmax 8.47e-05%, nfe).

*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 **322** lies in the egf-like 6; calcium-binding domain.

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.Val322Phe falls in the egf-like 6; calcium-binding 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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2021-09-17.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2020–2021); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-09-17 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2020-05-06 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Cardiovascular phenotype, 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.Val322Ile](/variant/efemp2-p-val322ile), [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 2026-10-14); 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 1381687). 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.*