# NM_007078.3(LDB3):c.1422G>A (p.Ser474=)

https://sugi.bio/variant/ldb3-p-ser474

## Summary

**LDB3 p.Ser474= (c.1422G>A)** is classified **Benign/Likely benign** in LDB3 (ClinVar, Multiple submitters, 15 submitters; last evaluated 2026-05-01). Rare (popmax 0.292%, nfe); Associated with Cardiovascular phenotype.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs142625982 · 15 submitters · 3 linked conditions · rare (popmax 0.292%, nfe)

## For patients & families {#patients}

This is a change in the LDB3 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 15 submitters, and is linked to Cardiovascular phenotype.

*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 | [LDB3](https://sugi.bio/atlas/gene/LDB3/) |
| Protein change (HGVS p.) | p.Ser474= |
| Coding change (HGVS c.) | c.1422G>A |
| MANE Select transcript | [NM_007078](https://www.ncbi.nlm.nih.gov/nuccore/NM_007078) |
| dbSNP | [rs142625982](https://www.ncbi.nlm.nih.gov/snp/rs142625982/) |
| Variant type | single nucleotide variant |
| Location | chr10:86716517-86716517 (GRCh38) |
| ClinVar | [VCV36444](https://www.ncbi.nlm.nih.gov/clinvar/variation/36444/) |

**All HGVS expressions:** `LRG_385:g.52954G>A`, `LRG_385t1:c.1422G>A`, `LRG_385t2:c.*17143G>A`, `NC_000010.10:g.88476274G>A`, `NC_000010.11:g.86716517G>A`, `NG_008876.1:g.52954G>A`, `NM_001080114.2:c.1092G>A`, `NM_001080116.1:c.*17143G>A`, `NM_001171610.2:c.1437G>A`, `NM_001368064.1:c.1233G>A`, `NM_001368065.1:c.1233G>A`, `NM_001368066.1:c.1281G>A`, `NM_007078.3:c.1422G>A`

## 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 gain** (Δ 0.46) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -10.275, GERP -2.48 — fast-evolving / accelerated position
- CADD: **PHRED 4.679**. 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 **0.26**, donor loss **0.00**, acceptor gain **0.46**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.46**, donor gain **0.00**.
- Pangolin: Δ**0.36** (gain), gain 0.36 / loss 0.00. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.292%** (nfe) · FAF95 0.284% · FAF99 0.281% · 3,444/1,179,244 in the highest group · 3,789/1,610,926 alleles overall — rare (popmax 0.292%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.292% | 342 |
| Remaining individuals (not grpmax-eligible) | 0.261% | 383 |
| Finnish (not grpmax-eligible) | 0.0849% | 1,178 |
| South Asian | 0.066% | 1,515 |
| African / African-American | 0.0568% | 1,760 |
| Admixed American | 0.0352% | 2,839 |
| Middle Eastern | 0.0165% | 6,052 |
| East Asian | 0.00671% | 14,893 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00338% | 29,578 |

*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}

Residue **474** lies in the 'disordered' region.

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. p.Ser474= falls in the disordered region.


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

**Molecular function:** cytoskeletal protein binding.

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-05-01.

**Submitter consensus:** conflicting (7 Likely benign, 6 Benign, 1 Likely Benign, 1 benign).

**Submission history:** 15 submissions (2015–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Likely benign | criteria provided, single submitter | clinical testing | 2015-02-18 |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Likely Benign | criteria provided, single submitter | clinical testing | 2025-03-11 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-01-26 |
| CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Likely benign | criteria provided, single submitter | clinical testing | 2018-01-26 |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2015-03-03 |
| Genome Diagnostics Laboratory, University Medical Center Utrecht | Likely benign | no assertion criteria provided | clinical testing |  |
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Likely benign | no assertion criteria provided | clinical testing |  |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Benign | criteria provided, single submitter | clinical testing | 2017-06-19 |
| Athena Diagnostics | benign | criteria provided, single submitter | clinical testing | 2024-01-31 |
| CeGaT Center for Human Genetics Tuebingen | Benign | criteria provided, single submitter | clinical testing | 2026-05-01 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-27 |
| Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | Likely benign | no assertion criteria provided | clinical testing |  |
| Clinical Genetics, Academic Medical Center | Benign | no assertion criteria provided | clinical testing |  |
| Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | Benign | no assertion criteria provided | clinical testing |  |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2015-12-15 |

## Associated conditions {#conditions}

[Cardiovascular phenotype](https://sugi.bio/atlas/disease/cardiovascular-phenotype/), [cardiomyopathy](https://sugi.bio/atlas/disease/cardiomyopathy/), [myofibrillar myopathy 4](https://sugi.bio/atlas/disease/myofibrillar-myopathy-4/).

**Reported phenotype names (ClinVar):** Cardiovascular phenotype, not specified, not provided, Cardiomyopathy, Myofibrillar myopathy 4, AllHighlyPenetrant, none provided, Cardiomyopathies, Zaspopathy (type).

## Similar variants {#similar}

Related LDB3 variant pages (same residue, condition, or type): [LDB3 p.Ser474Leu](/variant/ldb3-p-ser474leu), [LDB3 p.Ser474Pro](/variant/ldb3-p-ser474pro), [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).

### 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 36444). 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.*