# NM_001424.6(EMP2):c.285T>C (p.Phe95=)

https://sugi.bio/variant/emp2-p-phe95

## Summary

**EMP2 p.Phe95= (c.285T>C)** is classified **Likely benign** in EMP2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-06-01). Ultra-rare (popmax 0.015%, amr).

**At a glance:** Likely benign · review: Multiple submitters · rsID rs114697054 · 3 submitters · ultra-rare (popmax 0.015%, amr)

## For patients & families {#patients}

This is a change in the EMP2 gene that is classified as likely benign — not considered disease-causing, submitted by 3 submitters.

*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 | [EMP2](https://sugi.bio/atlas/gene/EMP2/) |
| Protein change (HGVS p.) | p.Phe95= |
| Coding change (HGVS c.) | c.285T>C |
| MANE Select transcript | [NM_001424](https://www.ncbi.nlm.nih.gov/nuccore/NM_001424) |
| dbSNP | [rs114697054](https://www.ncbi.nlm.nih.gov/snp/rs114697054/) |
| Variant type | single nucleotide variant |
| Location | chr16:10537959-10537959 (GRCh38) |
| ClinVar | [VCV2177903](https://www.ncbi.nlm.nih.gov/clinvar/variation/2177903/) |

**All HGVS expressions:** `NC_000016.10:g.10537959A>G`, `NC_000016.9:g.10631816A>G`, `NG_042058.1:g.47758T>C`, `NM_001424.5:c.285T>C`, `NM_001424.6:c.285T>C`

## 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 -0.233, GERP -4.49, phastCons 0.005 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 3.238**. 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: **below the reporting threshold**. This position is scored for a different substitution (A>T, Δ0.73 donor 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 (gnomAD v4.1): grpmax **0.015%** (amr) · FAF95 0.00773% · FAF99 0.00578% · 9/60,010 in the highest group · 21/1,614,150 alleles overall — ultra-rare (popmax 0.015%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.015% | 6,668 |
| Remaining individuals (not grpmax-eligible) | 0.0064% | 15,627 |
| European (non-Finnish) | 0.000678% | 147,504 |

*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}

**EMP2** population constraint: LOEUF 1.855, pLI 1.3258e-09, missense-Z -0.6926. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 94.89, 86% of residues very-high.

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

*Describes the biological roles of EMP2 (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:** EMP2's established molecular role includes integrin binding.


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

**Molecular function:** integrin binding, kinase binding.

**Biological process:** positive regulation of cell-matrix adhesion, regulation of glomerular filtration, apoptotic process, actin filament organization, cell adhesion, cell-matrix adhesion.

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-06-01.

**Submitter consensus:** unanimous (3/3 Likely benign).

**Submission history:** 3 submissions (2020–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2020-08-25 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-12-16 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2026-06-01 |

**Reported phenotype names (ClinVar):** not provided, EMP2-related disorder, none provided, EMP2-related condition.

## Similar variants {#similar}

Related EMP2 variant pages (same residue, condition, or type): [EMP2 p.Ala63Val](/variant/emp2-p-ala63val), [EMP2 p.Ala78Thr](/variant/emp2-p-ala78thr), [EMP2 p.Arg120His](/variant/emp2-p-arg120his), [EMP2 p.Arg166His](/variant/emp2-p-arg166his), [EMP2 p.Glu121Lys](/variant/emp2-p-glu121lys), [EMP2 p.Ile69Met](/variant/emp2-p-ile69met), [EMP2 p.Thr43Ile](/variant/emp2-p-thr43ile), [EMP2 p.Tyr143His](/variant/emp2-p-tyr143his).

### 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 2177903). 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.*