# NM_007078.3(LDB3):c.732C>G (p.Pro244=)

https://sugi.bio/variant/ldb3-p-pro244

## Summary

**LDB3 p.Pro244= (c.732C>G)** is classified **Uncertain significance** in LDB3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-10). Very rare (popmax 8.47e-05%, nfe); Associated with myofibrillar myopathy 4.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs144509718 · 1 submitter · 1 linked condition · very rare (popmax 8.47e-05%, nfe)

## For patients & families {#patients}

This is a change in the LDB3 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to myofibrillar myopathy 4.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant |
| Age of onset (of this condition) | Adult |
| Prevalence | <1 / 1 000 000 (Worldwide) |
| Diagnostic panels | LDB3 is a diagnostic-grade gene on 4 Genomics England panels |

**Commonly reported features of Late-onset distal myopathy, Markesbery-Griggs type** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Intrinsic hand muscle atrophy — Frequent (79-30%)
- Progressive proximal muscle weakness — Frequent (79-30%)
- Fatigable weakness of distal limb muscles — Frequent (79-30%)
- Abnormality of the cardiovascular system — Occasional (29-5%)
- Leg muscle stiffness — Occasional (29-5%)
- Weakness of the intrinsic hand muscles — Occasional (29-5%)
- Weakness of long finger extensor muscles — Occasional (29-5%)
- Wrist drop — Occasional (29-5%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0001886/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [LDB3](https://sugi.bio/atlas/gene/LDB3/) |
| Protein change (HGVS p.) | p.Pro244= |
| Coding change (HGVS c.) | c.732C>G |
| MANE Select transcript | [NM_007078](https://www.ncbi.nlm.nih.gov/nuccore/NM_007078) |
| dbSNP | [rs144509718](https://www.ncbi.nlm.nih.gov/snp/rs144509718/) |
| Variant type | single nucleotide variant |
| Location | chr10:86691938-86691938 (GRCh38) |
| ClinVar | [VCV2797942](https://www.ncbi.nlm.nih.gov/clinvar/variation/2797942/) |

**All HGVS expressions:** `LRG_385:g.28375C>G`, `LRG_385t1:c.732C>G`, `LRG_385t2:c.591C>G`, `NC_000010.10:g.88451695C>G`, `NC_000010.11:g.86691938C>G`, `NG_008876.1:g.28375C>G`, `NM_001080114.2:c.591C>G`, `NM_001080115.2:c.732C>G`, `NM_001080116.1:c.591C>G`, `NM_001171610.2:c.936C>G`, `NM_001171611.2:c.936C>G`, `NM_001368063.1:c.732C>G`, `NM_001368064.1:c.732C>G`, `NM_001368065.1:c.732C>G`, `NM_001368066.1:c.591C>G`, `NM_001368067.1:c.591C>G`, `NM_001368068.1:c.591C>G`, `NM_007078.3:c.732C>G`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor loss** (Δ 0.20) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP -20, GERP -4.87 — fast-evolving / accelerated position
- CADD: **PHRED 0.015**. 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.*
- SpliceAI deltas (raw): acceptor loss **0.20**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**. Largest is acceptor loss, 10 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **8.47e-05%** (nfe) · 1/1,180,036 in the highest group · 1/1,614,158 alleles overall — very rare (popmax 8.47e-05%, 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.*

## Gene constraint & dosage {#gene-context}

**LDB3** population constraint: LOEUF 0.864, pLI 1.5098e-11, missense-Z 0.90565. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **hypertrophic cardiomyopathy** — Disputed (AD)
- **dilated cardiomyopathy 1C** — Limited (AD)
- **arrhythmogenic right ventricular cardiomyopathy** — Disputed (AD)
- **cardiomyopathy, dilated, 2l** — Strong (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 61.98, 22% of residues very-high.

**2 experimental structure(s)** (PDB): [1RGW](https://www.rcsb.org/structure/1RGW), [4YDP](https://www.rcsb.org/structure/4YDP).

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

*Describes the biological roles of LDB3 (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:** LDB3's established molecular role includes cytoskeletal protein binding.


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

**Molecular function:** cytoskeletal protein binding.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-03-10.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-03-10 |

## Associated conditions {#conditions}

[myofibrillar myopathy 4](https://sugi.bio/atlas/disease/myofibrillar-myopathy-4/).

**Reported phenotype names (ClinVar):** Myofibrillar myopathy 4, Zaspopathy (type).

## Similar variants {#similar}

Related LDB3 variant pages (same residue, condition, or type): [LDB3 p.Pro244Ala](/variant/ldb3-p-pro244ala), [LDB3 p.Ala147Thr](/variant/ldb3-p-ala147thr), [LDB3 p.Ala165Val](/variant/ldb3-p-ala165val), [LDB3 c.1231+4A>C](/variant/ldb3-c-1231-plus-4a-c), [LDB3 c.1858-11C>A](/variant/ldb3-c-1858-minus-11c-a), [LDB3 c.246-3C>T](/variant/ldb3-c-246-minus-3c-t), [LDB3 c.322-1G>A](/variant/ldb3-c-322-minus-1g-a), [LDB3 c.859+3G>A](/variant/ldb3-c-859-plus-3g-a).

### 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 2797942). 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.*