# NM_020180.4(CELF4):c.1036C>T (p.Pro346Ser)

https://sugi.bio/variant/celf4-p-pro346ser

## Summary

**CELF4 p.Pro346Ser (c.1036C>T)** is classified **Uncertain significance** in CELF4 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-17). AlphaMissense: likely benign (0.0901); Ultra-rare (popmax 0.0165%, mid).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs769836710 · 1 submitter · AlphaMissense likely benign · ultra-rare (popmax 0.0165%, mid)

## For patients & families {#patients}

This is a change in the CELF4 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 | [CELF4](https://sugi.bio/atlas/gene/CELF4/) |
| Protein change (HGVS p.) | p.Pro346Ser |
| Coding change (HGVS c.) | c.1036C>T |
| MANE Select transcript | [NM_020180](https://www.ncbi.nlm.nih.gov/nuccore/NM_020180) |
| dbSNP | [rs769836710](https://www.ncbi.nlm.nih.gov/snp/rs769836710/) |
| Variant type | single nucleotide variant |
| Location | chr18:37270831-37270831 (GRCh38) |
| ClinVar | [VCV2250998](https://www.ncbi.nlm.nih.gov/clinvar/variation/2250998/) |

**All HGVS expressions:** `NC_000018.10:g.37270831G>A`, `NC_000018.9:g.34850794G>A`, `NM_001025087.2:c.1033C>T`, `NM_001025088.2:c.1030C>T`, `NM_001025089.2:c.1006C>T`, `NM_001330603.2:c.1033C>T`, `NM_001353695.2:c.1003C>T`, `NM_001353696.2:c.1033C>T`, `NM_001353697.2:c.1003C>T`, `NM_001353698.2:c.1033C>T`, `NM_001353699.2:c.1003C>T`, `NM_001353700.2:c.1006C>T`, `NM_001353702.2:c.1030C>T`, `NM_001353703.2:c.1006C>T`, `NM_001353705.2:c.1000C>T`, `NM_001353706.2:c.1000C>T`, `NM_001353707.2:c.1003C>T`, `NM_001353708.2:c.1036C>T`, `NM_001353709.2:c.1003C>T`, `NM_001353710.2:c.1006C>T`, `NM_001353711.2:c.1000C>T`, `NM_001353712.2:c.1030C>T`, `NM_001353713.2:c.1003C>T`, `NM_001353714.2:c.1003C>T`, `NM_001353715.2:c.1006C>T`, `NM_001353716.2:c.1030C>T`, `NM_001353717.2:c.1006C>T`, `NM_001353718.2:c.1033C>T`, `NM_001353719.2:c.1006C>T`, `NM_001353720.2:c.1006C>T`, `NM_001353721.2:c.1003C>T`, `NM_001353722.2:c.1000C>T`, `NM_001353723.2:c.1033C>T`, `NM_001353724.2:c.1036C>T`, `NM_001353725.2:c.1000C>T`, `NM_001353726.2:c.1003C>T`, `NM_001353727.2:c.1003C>T`, `NM_001353728.2:c.1003C>T`, `NM_001353729.2:c.1033C>T`, `NM_001353730.2:c.1033C>T`, `NM_001353731.2:c.1036C>T`, `NM_001353732.2:c.1003C>T`, `NM_001353733.2:c.1000C>T`, `NM_001353734.2:c.1036C>T`, `NM_001353735.2:c.1003C>T`, `NM_001353736.2:c.1036C>T`, `NM_001353737.2:c.1033C>T`, `NM_001353738.2:c.1033C>T`, `NM_001353739.2:c.1000C>T`, `NM_001353740.2:c.1036C>T`, `NM_001353741.2:c.1003C>T`, `NM_001353742.2:c.1033C>T`, `NM_001353743.2:c.1036C>T`, `NM_001353744.2:c.1036C>T`, `NM_001353745.2:c.1033C>T`, `NM_001353746.2:c.1033C>T`, `NM_001353747.2:c.1033C>T`, `NM_001353748.2:c.1006C>T`, `NM_001353749.2:c.1033C>T`, `NM_001353750.2:c.1003C>T`, `NM_001353751.2:c.1036C>T`, `NM_001353752.2:c.1003C>T`, `NM_001353753.2:c.1003C>T`, `NM_001353754.2:c.1030C>T`, `NM_001353755.2:c.1000C>T`, `NM_001353756.2:c.664C>T`, `NM_001353757.2:c.637C>T`, `NM_001353758.2:c.634C>T`, `NM_001353759.2:c.634C>T`, `NM_001353760.2:c.637C>T`, `NM_001353761.2:c.664C>T`, `NM_020180.4:c.1036C>T`, `NR_148518.2:n.1160C>T`, `NR_148519.2:n.1157C>T`, `NR_148520.2:n.1190C>T`, `NR_148521.2:n.1193C>T`, `NR_148522.2:n.1157C>T`, `NR_148523.2:n.1163C>T`, `NR_148524.2:n.1160C>T`, `NR_148525.2:n.1160C>T`, `NR_148526.2:n.1190C>T`, `NR_148527.2:n.1193C>T`, `NR_148528.2:n.1190C>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** (0.0901)
- REVEL 0.302 (indeterminate)
- SaProt LLR -8.551 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- Conservation: phyloP 11.779, GERP 2.2, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 26.6**. 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 0.75** across the covering region of the MANE Select transcript (37,253,814–37,274,378), spanning 20,564 bp. Chi-square p 4.4e-06. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>C, Δ0.49 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 **0.0165%** (mid) · FAF95 0.00145% · FAF99 0.00123% · 1/6,056 in the highest group · 26/1,461,552 alleles overall — ultra-rare (popmax 0.0165%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0165% | 6,056 |
| European (non-Finnish) | 0.00212% | 47,199 |

*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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-09-17.

**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 | 2021-09-17 |

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

## Similar variants {#similar}

Related CELF4 variant pages (same residue, condition, or type): [CELF4 p.Pro346fs](/variant/celf4-p-pro346fs), [CELF4 p.Gly193Val](/variant/celf4-p-gly193val), [CELF4 p.Ala381=](/variant/celf4-p-ala381), [CELF4 p.Pro127=](/variant/celf4-p-pro127), [CELF4 p.Pro406=](/variant/celf4-p-pro406), [CELF4 p.Glu76Ter](/variant/celf4-p-glu76ter), [CELF4 c.1165+2T>C](/variant/celf4-c-1165-plus-2t-c), [CELF4 c.370-67640C>A](/variant/celf4-c-370-minus-67640c-a).

### 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 2250998). 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.*