# NM_001375380.1(EBF3):c.537_544del (p.Pro180fs)

https://sugi.bio/variant/ebf3-p-pro180fs

## Summary

**EBF3 p.Pro180fs (c.537_544del)** is classified **Pathogenic** in EBF3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-18). No gnomAD frequency available for this variant; Associated with Inborn genetic diseases.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2493627848 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the EBF3 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to Inborn genetic diseases.

*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 | [EBF3](https://sugi.bio/atlas/gene/EBF3/) |
| Protein change (HGVS p.) | p.Pro180fs |
| Coding change (HGVS c.) | c.537_544del |
| MANE Select transcript | [NM_001375380](https://www.ncbi.nlm.nih.gov/nuccore/NM_001375380) |
| dbSNP | [rs2493627848](https://www.ncbi.nlm.nih.gov/snp/rs2493627848/) |
| Variant type | Deletion |
| Location | chr10:129957268-129957275 (GRCh38) |
| ClinVar | [VCV2265788](https://www.ncbi.nlm.nih.gov/clinvar/variation/2265788/) |

**All HGVS expressions:** `NC_000010.10:g.131755533_131755540del`, `NC_000010.11:g.129957269_129957276del`, `NG_030038.1:g.11553_11560del`, `NM_001005463.3:c.537_544del`, `NM_001375379.1:c.537_544del`, `NM_001375380.1:c.537_544del`, `NM_001375389.1:c.537_544del`, `NM_001375390.1:c.537_544del`, `NM_001375391.1:c.537_544del`, `NM_001375392.1:c.537_544del`

## 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 11.206, GERP 2.35, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene (constraint LOEUF 0.353, pLI 1), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 6 of 17**, 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}

**EBF3** population constraint: LOEUF 0.353, pLI 1, missense-Z 3.1501; ClinGen dosage — haploinsufficiency 3/3, triplosensitivity 0/3. *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):

- **hypotonia, ataxia, and delayed development syndrome** — Definitive (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 71.89, 45% of residues very-high.

**2 experimental structure(s)** (PDB): [3MUJ](https://www.rcsb.org/structure/3MUJ), [3N50](https://www.rcsb.org/structure/3N50).

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-01-18.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2022-01-18 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases.

## Similar variants {#similar}

Related EBF3 variant pages (same residue, condition, or type): [EBF3 p.Pro180His](/variant/ebf3-p-pro180his), [EBF3 p.Thr477fs](/variant/ebf3-p-thr477fs), [EBF3 c.289_291+1del](/variant/ebf3-c-289-291-plus-1del), [EBF3 p.Gln113fs](/variant/ebf3-p-gln113fs), [EBF3 c.1373-2del](/variant/ebf3-c-1373-minus-2del), [EBF3 p.Lys168del](/variant/ebf3-p-lys168del), [EBF3 p.Pro180Ser](/variant/ebf3-p-pro180ser), [EBF3 p.Tyr391_Met393delinsLeu](/variant/ebf3-p-tyr391-met393delinsleu).

### 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 2265788). 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.*