# NM_031889.3(ENAM):c.372_382del (p.Lys124fs)

https://sugi.bio/variant/enam-p-lys124fs

## Summary

**ENAM p.Lys124fs (c.372_382del)** is classified **Likely pathogenic** in ENAM (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-21). No gnomAD frequency available for this variant.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs2545343550 · 1 submitter · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the ENAM gene that is considered likely disease-causing, 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 | [ENAM](https://sugi.bio/atlas/gene/ENAM/) |
| Protein change (HGVS p.) | p.Lys124fs |
| Coding change (HGVS c.) | c.372_382del |
| MANE Select transcript | [NM_031889](https://www.ncbi.nlm.nih.gov/nuccore/NM_031889) |
| dbSNP | [rs2545343550](https://www.ncbi.nlm.nih.gov/snp/rs2545343550/) |
| Variant type | Deletion |
| Location | chr4:70634468-70634478 (GRCh38) |
| ClinVar | [VCV2440040](https://www.ncbi.nlm.nih.gov/clinvar/variation/2440040/) |

**All HGVS expressions:** `LRG_1348:g.10726_10736del`, `LRG_1348t1:c.372_382del`, `NC_000004.11:g.71500186_71500196del`, `NC_000004.12:g.70634469_70634479del`, `NG_013024.1:g.10726_10736del`, `NM_031889.3:c.372_382del`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 4.52, GERP 1.71, phastCons 0.999 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.892, pLI 0.0011786. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 6 of 9**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion 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}

**ENAM** population constraint: LOEUF 0.892, pLI 0.0011786, missense-Z 0.61748. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **124** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 36.63, 0% of residues very-high.

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

*Describes the biological roles of ENAM (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.*


### Pathways affected {#pathways}

ENAM participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Post-translational protein phosphorylation](https://reactome.org/content/detail/R-HSA-8957275) | curated |
| [Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)](https://reactome.org/content/detail/R-HSA-381426) | curated |

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-03-21.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Revvity Omics, Revvity | Likely pathogenic | criteria provided, single submitter | clinical testing | 2022-03-21 |

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

## Similar variants {#similar}

Related ENAM variant pages (same residue, condition, or type): [ENAM c.588+1del](/variant/enam-c-588-plus-1del), [ENAM p.Asp921fs](/variant/enam-p-asp921fs), [ENAM p.Asn36fs](/variant/enam-p-asn36fs), [ENAM p.Asn628fs](/variant/enam-p-asn628fs), [ENAM p.Ser312fs](/variant/enam-p-ser312fs), [ENAM c.123+3_123+6del](/variant/enam-c-123-plus-3-123-plus-6del), [ENAM p.Phe1002fs](/variant/enam-p-phe1002fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); 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 2440040). 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.*