# NM_001375380.1(EBF3):c.1398C>T (p.Ser466=)

https://sugi.bio/variant/ebf3-p-ser466

## Summary

**EBF3 p.Ser466= (c.1398C>T)** is classified **Likely benign** in EBF3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-23). Very rare (popmax 0.00169%, amr).

**At a glance:** Likely benign · review: Single submitter · 1 submitter · very rare (popmax 0.00169%, amr)

## For patients & families {#patients}

This is a change in the EBF3 gene that is classified as likely benign — not considered 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 | [EBF3](https://sugi.bio/atlas/gene/EBF3/) |
| Protein change (HGVS p.) | p.Ser466= |
| Coding change (HGVS c.) | c.1398C>T |
| MANE Select transcript | [NM_001375380](https://www.ncbi.nlm.nih.gov/nuccore/NM_001375380) |
| Variant type | single nucleotide variant |
| Location | chr10:129841007-129841007 (GRCh38) |
| ClinVar | [VCV4909934](https://www.ncbi.nlm.nih.gov/clinvar/variation/4909934/) |

**All HGVS expressions:** `NC_000010.10:g.131639271G>A`, `NC_000010.11:g.129841007G>A`, `NG_030038.1:g.127821C>T`, `NM_001005463.3:c.1371C>T`, `NM_001375379.1:c.1398C>T`, `NM_001375380.1:c.1398C>T`, `NM_001375389.1:c.1398C>T`, `NM_001375390.1:c.1371C>T`, `NM_001375391.1:c.1398C>T`, `NM_001375392.1:c.1346-565C>T`

## 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 6.45, GERP 1.92, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 13.56**. 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 (G>C, Δ0.20 acceptor loss), 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 **0.00169%** (amr) · FAF95 0.000764% · FAF99 0.000606% · 1/59,220 in the highest group · 17/1,608,174 alleles overall — very rare (popmax 0.00169%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00169% | 59,220 |
| Finnish (not grpmax-eligible) | 0.00161% | 62,208 |
| European (non-Finnish) | 0.00127% | 78,568 |

*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}

Residue **466** lies in the 'disordered' region.

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 benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-11-23.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2022-11-23 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related EBF3 variant pages (same residue, condition, or type): [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.Arg152Gly](/variant/ebf3-p-arg152gly), [EBF3 p.Arg163Gln](/variant/ebf3-p-arg163gln), [EBF3 p.Arg163Leu](/variant/ebf3-p-arg163leu), [EBF3 p.Arg163Trp](/variant/ebf3-p-arg163trp), [EBF3 p.Arg206Ter](/variant/ebf3-p-arg206ter), [EBF3 p.Arg209Gln](/variant/ebf3-p-arg209gln).

### 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 4909934). 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.*