# NM_001113407.3(LDB1):c.990del (p.Ser331fs)

https://sugi.bio/variant/ldb1-p-ser331fs

## Summary

**LDB1 p.Ser331fs (c.990del)** is classified **Uncertain significance** in LDB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-22).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter

## For patients & families {#patients}

This is a change in the LDB1 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 | [LDB1](https://sugi.bio/atlas/gene/LDB1/) |
| Protein change (HGVS p.) | p.Ser331fs |
| Coding change (HGVS c.) | c.990del |
| MANE Select transcript | [NM_001113407](https://www.ncbi.nlm.nih.gov/nuccore/NM_001113407) |
| Variant type | Deletion |
| Location | chr10:102109044-102109044 (GRCh38) |
| ClinVar | [VCV3602231](https://www.ncbi.nlm.nih.gov/clinvar/variation/3602231/) |

**All HGVS expressions:** `NC_000010.10:g.103868801del`, `NC_000010.11:g.102109044del`, `NM_001113407.3:c.990del`, `NM_001321612.2:c.990del`, `NM_003893.5:c.882del`

## 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 11.298, GERP 0.974, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. the gene is **loss-of-function-intolerant** (LOEUF 0.24, pLI 1), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **within the last 50 nt of the penultimate exon (10 of 11, 15 nt from its 3' end)** — 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 deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.

*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}

**LDB1** population constraint: LOEUF 0.24, pLI 1, missense-Z 3.4853. *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 72.04, 45% of residues very-high.

**9 experimental structure(s)** (PDB): [2XJY](https://www.rcsb.org/structure/2XJY), [2XJZ](https://www.rcsb.org/structure/2XJZ), [2YPA](https://www.rcsb.org/structure/2YPA), [6TYD](https://www.rcsb.org/structure/6TYD), [7OB5](https://www.rcsb.org/structure/7OB5), [7OB8](https://www.rcsb.org/structure/7OB8).

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

*Describes the biological roles of LDB1 (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:** LDB1's established molecular role includes enzyme binding.


### Pathways affected {#pathways}

LDB1 participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Cardiogenesis](https://reactome.org/content/detail/R-HSA-9733709) | other |
| [Expression and translocation of olfactory receptors](https://reactome.org/content/detail/R-HSA-9752946) | other |
| [RUNX1 regulates transcription of genes involved in differentiation of HSCs](https://reactome.org/content/detail/R-HSA-8939236) | other |
| [Regulation of expression of SLITs and ROBOs](https://reactome.org/content/detail/R-HSA-9010553) | other |

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

**Molecular function:** enzyme binding, LIM domain binding, RNA polymerase II-specific DNA-binding transcription factor binding, DNA-binding transcription factor binding.

**Biological process:** negative regulation of DNA-templated transcription, positive regulation of transcription by RNA polymerase II.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-05-22.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-05-22 |

**Reported phenotype names (ClinVar):** not provided, none provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM.

## Similar variants {#similar}

Related LDB1 variant pages (same residue, condition, or type): [LDB1 p.Arg356fs](/variant/ldb1-p-arg356fs), [LDB1 p.Glu349fs](/variant/ldb1-p-glu349fs), [LDB1 p.Ser317fs](/variant/ldb1-p-ser317fs), [LDB1 p.Gln66fs](/variant/ldb1-p-gln66fs), [LDB1 p.Thr67fs](/variant/ldb1-p-thr67fs), [LDB1 p.Val334fs](/variant/ldb1-p-val334fs).

### 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 3602231). 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.*