# NM_001395167.1(EBF4):c.1775C>T (p.Pro592Leu)

https://sugi.bio/variant/ebf4-p-pro592leu

## Summary

**EBF4 p.Pro592Leu (c.1775C>T)** is classified **Uncertain significance** in EBF4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-06). AlphaMissense: likely benign (0.1085); Very rare (popmax 0.00427%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs374623419 · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.00427%, nfe)

## For patients & families {#patients}

This is a change in the EBF4 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, 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 | [EBF4](https://sugi.bio/atlas/gene/EBF4/) |
| Protein change (HGVS p.) | p.Pro592Leu |
| Coding change (HGVS c.) | c.1775C>T |
| MANE Select transcript | [NM_001395167](https://www.ncbi.nlm.nih.gov/nuccore/NM_001395167) |
| dbSNP | [rs374623419](https://www.ncbi.nlm.nih.gov/snp/rs374623419/) |
| Variant type | single nucleotide variant |
| Location | chr20:2758945-2758945 (GRCh38) |
| ClinVar | [VCV2206893](https://www.ncbi.nlm.nih.gov/clinvar/variation/2206893/) |

**All HGVS expressions:** `NC_000020.10:g.2739591C>T`, `NC_000020.11:g.2758945C>T`, `NM_001110514.2:c.2075C>T`, `NM_001395167.1:c.1775C>T`, `NM_001395168.1:c.1544C>T`, `NR_138537.2:n.2013C>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.1085)
- REVEL 0.065 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.649 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **donor loss** (Δ 0.22) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 5.901, GERP 0.68, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 23.5**. 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 1.06** across the covering region of the MANE Select transcript (2,749,647–2,758,976), spanning 9,329 bp. Chi-square p 0.2. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.17**, donor loss **0.22**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss.
- SpliceAI deltas (masked): acceptor loss **0.17**, donor loss **0.22**, acceptor gain **0.00**, donor gain **0.00**.
- Pangolin: Δ**0.33** (loss), gain 0.00 / loss 0.33. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00427%** (nfe) · FAF95 0.00327% · FAF99 0.00295% · 49/1,147,018 in the highest group · 51/1,551,708 alleles overall — very rare (popmax 0.00427%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00427% | 23,409 |
| Remaining individuals (not grpmax-eligible) | 0.00166% | 60,120 |
| African / African-American | 0.00137% | 73,048 |

*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}

**EBF4** population constraint: LOEUF 0.868, pLI 2.4171e-07, missense-Z -1.8613. *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 **592** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 72.60, 47% of residues very-high.

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

*Describes the biological roles of EBF4 (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:** EBF4's established molecular role includes RNA polymerase II cis-regulatory region sequence-specific DNA binding. p.Pro592Leu falls in the disordered region.


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

**Molecular function:** RNA polymerase II cis-regulatory region sequence-specific DNA binding, DNA-binding transcription factor activity, RNA polymerase II-specific, DNA-binding transcription factor binding.

**Biological process:** positive regulation of transcription by RNA polymerase II, T cell apoptotic process.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-09-06.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-09-06 |

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

## Similar variants {#similar}

Related EBF4 variant pages (same residue, condition, or type): [EBF4 p.Arg164=](/variant/ebf4-p-arg164), [EBF4 p.Ile91=](/variant/ebf4-p-ile91), [EBF4 p.Ala102Thr](/variant/ebf4-p-ala102thr), [EBF4 p.Ala102Val](/variant/ebf4-p-ala102val), [EBF4 p.Ala402Thr](/variant/ebf4-p-ala402thr), [EBF4 p.Ala40Thr](/variant/ebf4-p-ala40thr), [EBF4 p.Ala438Ser](/variant/ebf4-p-ala438ser), [EBF4 p.Ala522Val](/variant/ebf4-p-ala522val).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 2206893). 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.*