# NM_001042603.3(KDM5A):c.4395dup (p.Trp1466fs)

https://sugi.bio/variant/kdm5a-p-trp1466fs

## Summary

**KDM5A p.Trp1466fs (c.4395dup)** is classified **Uncertain significance** in KDM5A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-26).

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

## For patients & families {#patients}

This is a change in the KDM5A 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 | [KDM5A](https://sugi.bio/atlas/gene/KDM5A/) |
| Protein change (HGVS p.) | p.Trp1466fs |
| Coding change (HGVS c.) | c.4395dup |
| MANE Select transcript | [NM_001042603](https://www.ncbi.nlm.nih.gov/nuccore/NM_001042603) |
| Variant type | Duplication |
| Location | chr12:295632-295633 (GRCh38) |
| ClinVar | [VCV3368463](https://www.ncbi.nlm.nih.gov/clinvar/variation/3368463/) |

**All HGVS expressions:** `NC_000012.11:g.404799dup`, `NC_000012.12:g.295633dup`, `NG_046993.1:g.98823dup`, `NM_001042603.3:c.4395dup`

## 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 11.202, GERP 1.69, 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 0.27, pLI 1), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 26 of 28**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication 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}

**KDM5A** population constraint: LOEUF 0.27, pLI 1, missense-Z 3.6096. *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):

- **congenital heart disease** — Limited (AD)

## Protein context {#protein}

Residue **1466** lies in a UniProt-annotated variant site (found in a patient with severe intellectual disability, developmental delay, focal epilepsy, tetraspastic gait, ataxia and behavioral difficulties; uncertain significance).

AlphaFold model confidence (whole protein): pLDDT 70.98, 28% of residues very-high.

**46 experimental structure(s)** (PDB): [2JXJ](https://www.rcsb.org/structure/2JXJ), [2KGG](https://www.rcsb.org/structure/2KGG), [2KGI](https://www.rcsb.org/structure/2KGI), [3GL6](https://www.rcsb.org/structure/3GL6), [5C11](https://www.rcsb.org/structure/5C11), [5CEH](https://www.rcsb.org/structure/5CEH).

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

*Describes the biological roles of KDM5A (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:** KDM5A's established molecular role includes transcription cis-regulatory region binding.


### Pathways affected {#pathways}

KDM5A participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [HDMs demethylate histones](https://reactome.org/content/detail/R-HSA-3214842) | curated |
| [Chromatin modifications during the maternal to zygotic transition (MZT)](https://reactome.org/content/detail/R-HSA-9821002) | electronic |

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

**Molecular function:** transcription cis-regulatory region binding, DNA binding, zinc ion binding, histone H3K4me/H3K4me2/H3K4me3 demethylase activity, histone binding.

**Biological process:** transcription initiation-coupled chromatin remodeling, positive regulation of DNA-templated transcription.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-01-26.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-01-26 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related KDM5A variant pages (same residue, condition, or type): [KDM5A p.Trp1466Arg](/variant/kdm5a-p-trp1466arg), [KDM5A c.2151-14_2151-5dup](/variant/kdm5a-c-2151-minus-14-2151-minus-5dup), [KDM5A c.2151-15_2151-5dup](/variant/kdm5a-c-2151-minus-15-2151-minus-5dup), [KDM5A p.Tyr9fs](/variant/kdm5a-p-tyr9fs), [KDM5A c.2151-10_2151-5dup](/variant/kdm5a-c-2151-minus-10-2151-minus-5dup), [KDM5A c.2151-13_2151-5dup](/variant/kdm5a-c-2151-minus-13-2151-minus-5dup), [KDM5A c.2151-16_2151-5dup](/variant/kdm5a-c-2151-minus-16-2151-minus-5dup), [KDM5A c.2151-17_2151-5dup](/variant/kdm5a-c-2151-minus-17-2151-minus-5dup).

### 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 3368463). 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.*