# NM_001375380.1(EBF3):c.455G>C (p.Arg152Pro)

https://sugi.bio/variant/ebf3-p-arg152pro

## Summary

**EBF3 p.Arg152Pro (c.455G>C)** is classified **Likely pathogenic** in EBF3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-26). AlphaMissense: likely pathogenic (0.9998); Absent from gnomAD v4.1; Associated with hypotonia, ataxia, and delayed development syndrome.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs2493642124 · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the EBF3 gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to hypotonia, ataxia, and delayed development syndrome.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0025054/index) · [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.Arg152Pro |
| Coding change (HGVS c.) | c.455G>C |
| MANE Select transcript | [NM_001375380](https://www.ncbi.nlm.nih.gov/nuccore/NM_001375380) |
| dbSNP | [rs2493642124](https://www.ncbi.nlm.nih.gov/snp/rs2493642124/) |
| Variant type | single nucleotide variant |
| Location | chr10:129958964-129958964 (GRCh38) |
| ClinVar | [VCV3065192](https://www.ncbi.nlm.nih.gov/clinvar/variation/3065192/) |

**All HGVS expressions:** `NC_000010.10:g.131757228C>G`, `NC_000010.11:g.129958964C>G`, `NG_030038.1:g.9864G>C`, `NG_121136.1:g.827C>G`, `NM_001005463.3:c.455G>C`, `NM_001375379.1:c.455G>C`, `NM_001375380.1:c.455G>C`, `NM_001375389.1:c.455G>C`, `NM_001375390.1:c.455G>C`, `NM_001375391.1:c.455G>C`, `NM_001375392.1:c.455G>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9998) — concordant with the pathogenic call
- REVEL 0.63 (indeterminate)
- SaProt LLR -17.419 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL is indeterminate
- Conservation: phyloP 7.356, GERP 2.3, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 34.0**. 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 0.16** across the covering region of the MANE Select transcript (129,873,595–129,958,981), spanning 85,386 bp — the region is depleted of missense variation. Chi-square p 4.3e-15. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- 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}

**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}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-03-26.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-03-26 |

## Associated conditions {#conditions}

[hypotonia, ataxia, and delayed development syndrome](https://sugi.bio/atlas/disease/hypotonia-ataxia-and-delayed-development-syndrome/).

**Reported phenotype names (ClinVar):** Hypotonia, ataxia, and delayed development syndrome, EBF3 Neurodevelopmental Disorder.

## Same-residue context {#hotspot}

Residue **152** carries **3 other pathogenic ClinVar variants** — a recurrently-mutated position: [EBF3 p.Arg152Gly](/variant/ebf3-p-arg152gly), [EBF3 p.Arg152Cys](/variant/ebf3-p-arg152cys), [EBF3 p.Arg152Leu](/variant/ebf3-p-arg152leu). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related EBF3 variant pages (same residue, condition, or type): [EBF3 p.Arg152Cys](/variant/ebf3-p-arg152cys), [EBF3 p.Arg152Leu](/variant/ebf3-p-arg152leu), [EBF3 p.Arg152Gly](/variant/ebf3-p-arg152gly), [EBF3 c.486-1G>A](/variant/ebf3-c-486-minus-1g-a), [EBF3 c.555-2A>G](/variant/ebf3-c-555-minus-2a-g), [EBF3 p.Arg163Gln](/variant/ebf3-p-arg163gln), [EBF3 p.Arg163Leu](/variant/ebf3-p-arg163leu), [EBF3 p.Arg163Trp](/variant/ebf3-p-arg163trp).

### 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 3065192). 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.*