# NM_020180.4(CELF4):c.1037del (p.Pro346fs)

https://sugi.bio/variant/celf4-p-pro346fs

## Summary

**CELF4 p.Pro346fs (c.1037del)** is classified **Conflicting classifications of pathogenicity** in CELF4 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-05-05). No allele count reported in gnomAD v4.1 (AN 1,613,782); Associated with neurodevelopmental disorder.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · 2 submitters · 1 linked condition · no allele count reported in gnomAD v4.1 (AN 1,613,782)

## For patients & families {#patients}

This is a change in the CELF4 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 2 submitters, and is linked to neurodevelopmental disorder.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 210 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CELF4](https://sugi.bio/atlas/gene/CELF4/) |
| Protein change (HGVS p.) | p.Pro346fs |
| Coding change (HGVS c.) | c.1037del |
| MANE Select transcript | [NM_020180](https://www.ncbi.nlm.nih.gov/nuccore/NM_020180) |
| Variant type | Deletion |
| Location | chr18:37270830-37270830 (GRCh38) |
| ClinVar | [VCV3362794](https://www.ncbi.nlm.nih.gov/clinvar/variation/3362794/) |

**All HGVS expressions:** `NC_000018.10:g.37270835del`, `NC_000018.9:g.34850798del`, `NM_001025087.2:c.1034del`, `NM_001025088.2:c.1031del`, `NM_001025089.2:c.1007del`, `NM_001330603.2:c.1034del`, `NM_001353695.2:c.1004del`, `NM_001353696.2:c.1034del`, `NM_001353697.2:c.1004del`, `NM_001353698.2:c.1034del`, `NM_001353699.2:c.1004del`, `NM_001353700.2:c.1007del`, `NM_001353702.2:c.1031del`, `NM_001353703.2:c.1007del`, `NM_001353705.2:c.1001del`, `NM_001353706.2:c.1001del`, `NM_001353707.2:c.1004del`, `NM_001353708.2:c.1037del`, `NM_001353709.2:c.1004del`, `NM_001353710.2:c.1007del`, `NM_001353711.2:c.1001del`, `NM_001353712.2:c.1031del`, `NM_001353713.2:c.1004del`, `NM_001353714.2:c.1004del`, `NM_001353715.2:c.1007del`, `NM_001353716.2:c.1031del`, `NM_001353717.2:c.1007del`, `NM_001353718.2:c.1034del`, `NM_001353719.2:c.1007del`, `NM_001353720.2:c.1007del`, `NM_001353721.2:c.1004del`, `NM_001353722.2:c.1001del`, `NM_001353723.2:c.1034del`, `NM_001353724.2:c.1037del`, `NM_001353725.2:c.1001del`, `NM_001353726.2:c.1004del`, `NM_001353727.2:c.1004del`, `NM_001353728.2:c.1004del`, `NM_001353729.2:c.1034del`, `NM_001353730.2:c.1034del`, `NM_001353731.2:c.1037del`, `NM_001353732.2:c.1004del`, `NM_001353733.2:c.1001del`, `NM_001353734.2:c.1037del`, `NM_001353735.2:c.1004del`, `NM_001353736.2:c.1037del`, `NM_001353737.2:c.1034del`, `NM_001353738.2:c.1034del`, `NM_001353739.2:c.1001del`, `NM_001353740.2:c.1037del`, `NM_001353741.2:c.1004del`, `NM_001353742.2:c.1034del`, `NM_001353743.2:c.1037del`, `NM_001353744.2:c.1037del`, `NM_001353745.2:c.1034del`, `NM_001353746.2:c.1034del`, `NM_001353747.2:c.1034del`, `NM_001353748.2:c.1007del`, `NM_001353749.2:c.1034del`, `NM_001353750.2:c.1004del`, `NM_001353751.2:c.1037del`, `NM_001353752.2:c.1004del`, `NM_001353753.2:c.1004del`, `NM_001353754.2:c.1031del`, `NM_001353755.2:c.1001del`, `NM_001353756.2:c.665del`, `NM_001353757.2:c.638del`, `NM_001353758.2:c.635del`, `NM_001353759.2:c.635del`, `NM_001353760.2:c.638del`, `NM_001353761.2:c.665del`, `NM_020180.3:c.1037del`, `NM_020180.4:c.1037del`, `NR_148518.2:n.1161del`, `NR_148519.2:n.1158del`, `NR_148520.2:n.1191del`, `NR_148521.2:n.1194del`, `NR_148522.2:n.1158del`, `NR_148523.2:n.1164del`, `NR_148524.2:n.1161del`, `NR_148525.2:n.1161del`, `NR_148526.2:n.1191del`, `NR_148527.2:n.1194del`, `NR_148528.2:n.1191del`

## 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 1.491, GERP -1.92, phastCons 1 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.546, pLI 0.83578. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 8 of 13**, 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 allele count reported in gnomAD v4.1 (AN 1,613,782)** — 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}

**CELF4** population constraint: LOEUF 0.546, pLI 0.83578, missense-Z 2.8751; ClinGen dosage — haploinsufficiency 1, triplosensitivity 0 (0–3 scale). *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 62.70, 23% of residues very-high.

**2 experimental structure(s)** (PDB): [2DGP](https://www.rcsb.org/structure/2DGP), [2DNK](https://www.rcsb.org/structure/2DNK).

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

*Describes the biological roles of CELF4 (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:** CELF4's established molecular role includes pre-mRNA binding.


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

**Molecular function:** pre-mRNA binding.

**Biological process:** alternative mRNA splicing, via spliceosome, regulation of alternative mRNA splicing, via spliceosome, positive regulation of mRNA splicing, via spliceosome.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-05-05.

**Submitter consensus:** conflicting (1 Uncertain significance, 1 Pathogenic).

**Submission history:** 2 submissions (2024–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | Uncertain significance | criteria provided, single submitter | research | 2024-09-24 |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2025-05-05 |

## Associated conditions {#conditions}

[neurodevelopmental disorder](https://sugi.bio/atlas/disease/neurodevelopmental-disorder/).

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

## Similar variants {#similar}

Related CELF4 variant pages (same residue, condition, or type): [CELF4 c.287-5_300del](/variant/celf4-c-287-minus-5-300del), [CELF4 p.Pro346Ser](/variant/celf4-p-pro346ser), [CELF4 p.Gly193Val](/variant/celf4-p-gly193val), [CELF4 c.370-67640C>A](/variant/celf4-c-370-minus-67640c-a), [CELF4 c.577+2T>G](/variant/celf4-c-577-plus-2t-g), [CELF4 p.Arg138Ter](/variant/celf4-p-arg138ter), [CELF4 p.Cys194Ter](/variant/celf4-p-cys194ter), [CELF4 p.Gln271Ter](/variant/celf4-p-gln271ter).

### 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 3362794). 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.*