# NM_001012968.3(SPIN4):c.312_313del (p.Arg104fs)

https://sugi.bio/variant/spin4-p-arg104fs

## Summary

**SPIN4 p.Arg104fs (c.312_313del)** is classified **Pathogenic** in SPIN4 (ClinVar, Single submitter, 2 submitters; last evaluated 2024-05-30). Very rare (popmax 0.000112%, nfe); Associated with Lui-Jee-Baron syndrome.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2519642745 · 2 submitters · 1 linked condition · very rare (popmax 0.000112%, nfe)

## For patients & families {#patients}

This is a change in the SPIN4 gene that is reported as disease-causing, but on limited review, submitted by 2 submitters, and is linked to Lui-Jee-Baron 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:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [SPIN4](https://sugi.bio/atlas/gene/SPIN4/) |
| Protein change (HGVS p.) | p.Arg104fs |
| Coding change (HGVS c.) | c.312_313del |
| MANE Select transcript | [NM_001012968](https://www.ncbi.nlm.nih.gov/nuccore/NM_001012968) |
| dbSNP | [rs2519642745](https://www.ncbi.nlm.nih.gov/snp/rs2519642745/) |
| Variant type | Microsatellite |
| Location | chrX:63350507-63350508 (GRCh38) |
| ClinVar | [VCV2671851](https://www.ncbi.nlm.nih.gov/clinvar/variation/2671851/) |

**All HGVS expressions:** `NC_000023.10:g.62570387TC[2]`, `NC_000023.11:g.63350508TC[2]`, `NG_202776.1:g.88TC[2]`, `NM_001012968.3:c.312_313del`, `NM_001012968.3:c.312_313delAG`

## Computational & population evidence {#evidence}

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

- **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 9.683, GERP 1.85, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in the last exon (1 of 1)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no microsatellite variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.000112%** (nfe) · 1/895,362 in the highest group · 1/1,211,195 alleles overall — very rare (popmax 0.000112%, nfe).

*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.*

## Protein context {#protein}

Residue **104** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 82.17, 64% of residues very-high.

**2 experimental structure(s)** (PDB): [4UY4](https://www.rcsb.org/structure/4UY4), [9T31](https://www.rcsb.org/structure/9T31).

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

*Describes the biological roles of SPIN4 (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:** SPIN4's established molecular role includes histone H3K4me3 reader activity.


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

**Molecular function:** histone H3K4me3 reader activity.

**Biological process:** negative regulation of cell population proliferation, positive regulation of canonical Wnt signaling pathway.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-05-30.

**Submitter consensus:** unanimous (2/2 Pathogenic).

**Submission history:** 2 submissions (2023–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2023-12-18 |
| Genetics and Personalized Medicine Clinic, Tartu University Hospital | Pathogenic | criteria provided, single submitter | clinical testing | 2024-05-30 |

## Associated conditions {#conditions}

[Lui-Jee-Baron syndrome](https://sugi.bio/atlas/disease/lui-jee-baron-syndrome/).

**Reported phenotype names (ClinVar):** Lui-Jee-Baron syndrome.

## Similar variants {#similar}

Related SPIN4 variant pages (same residue, condition, or type): [SPIN4 p.Val242Asp](/variant/spin4-p-val242asp).

### 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 2671851). 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.*