# NM_001009999.3(KDM1A):c.459A>G (p.Pro153=)

https://sugi.bio/variant/kdm1a-p-pro153

## Summary

**KDM1A p.Pro153= (c.459A>G)** is classified **Likely benign** in KDM1A (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-11-30). Very rare (popmax 0.00223%, eas); Associated with Inborn genetic diseases.

**At a glance:** Likely benign · review: Multiple submitters · 3 submitters · 1 linked condition · very rare (popmax 0.00223%, eas)

## For patients & families {#patients}

This is a change in the KDM1A gene that is classified as likely benign — not considered disease-causing, submitted by 3 submitters, and is linked to Inborn genetic diseases.

*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 | [KDM1A](https://sugi.bio/atlas/gene/KDM1A/) |
| Protein change (HGVS p.) | p.Pro153= |
| Coding change (HGVS c.) | c.459A>G |
| MANE Select transcript | [NM_001009999](https://www.ncbi.nlm.nih.gov/nuccore/NM_001009999) |
| Variant type | single nucleotide variant |
| Location | chr1:23030576-23030576 (GRCh38) |
| ClinVar | [VCV3257233](https://www.ncbi.nlm.nih.gov/clinvar/variation/3257233/) |

**All HGVS expressions:** `NC_000001.10:g.23357069A>G`, `NC_000001.11:g.23030576A>G`, `NG_047129.1:g.16134A>G`, `NM_001009999.2:c.459A>G`, `NM_001009999.3:c.459A>G`, `NM_001363654.2:c.459A>G`, `NM_001410762.1:c.459A>G`, `NM_001410763.1:c.459A>G`, `NM_015013.4:c.459A>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 (below), not from a missing predictor score.
- Conservation: phyloP -3.831, GERP -3.93 — fast-evolving / accelerated position
- CADD: **PHRED 1.325**. 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: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00223%** (eas) · FAF95 0.000501% · FAF99 0.000366% · 1/44,762 in the highest group · 12/1,610,782 alleles overall — very rare (popmax 0.00223%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.00223% | 44,762 |
| European (non-Finnish) | 0.000933% | 107,162 |

*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}

**KDM1A** population constraint: LOEUF 0.638, pLI 0.003442, missense-Z 3.796. *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):

- **palatal anomalies-widely spaced teeth-facial dysmorphism-developmental delay syndrome** — Definitive (AD)

## Protein context {#protein}

Residue **153** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 85.29, 78% of residues very-high.

**129 experimental structure(s)** (PDB): [2COM](https://www.rcsb.org/structure/2COM), [2DW4](https://www.rcsb.org/structure/2DW4), [2EJR](https://www.rcsb.org/structure/2EJR), [2H94](https://www.rcsb.org/structure/2H94), [2HKO](https://www.rcsb.org/structure/2HKO), [2IW5](https://www.rcsb.org/structure/2IW5) — incl. mutant structure 2X0L.

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

*Describes the biological roles of KDM1A (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:** KDM1A's established molecular role includes p53 binding. p.Pro153= falls in the disordered region. In Reactome, KDM1A is annotated in disease pathway(s) including **Potential therapeutics for SARS**.

**Disease mechanism (Reactome):** KDM1A loss or alteration is curated in [Potential therapeutics for SARS](https://reactome.org/content/detail/R-HSA-9679191).

### Pathways affected {#pathways}

KDM1A participates in **9 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Potential therapeutics for SARS](https://reactome.org/content/detail/R-HSA-9679191) | curated |
| [Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3](https://reactome.org/content/detail/R-HSA-5625886) | curated |
| [Estrogen-dependent gene expression](https://reactome.org/content/detail/R-HSA-9018519) | curated |
| [Factors involved in megakaryocyte development and platelet production](https://reactome.org/content/detail/R-HSA-983231) | curated |
| [HDACs deacetylate histones](https://reactome.org/content/detail/R-HSA-3214815) | curated |
| [HDMs demethylate histones](https://reactome.org/content/detail/R-HSA-3214842) | curated |
| [NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux](https://reactome.org/content/detail/R-HSA-9029569) | curated |
| [Negative Regulation of CDH1 Gene Transcription](https://reactome.org/content/detail/R-HSA-9764725) | curated |
| [Regulation of PTEN gene transcription](https://reactome.org/content/detail/R-HSA-8943724) | electronic |

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

**Molecular function:** p53 binding, chromatin binding, transcription coactivator activity, transcription corepressor activity, oxidoreductase activity, enzyme binding.

**Biological process:** negative regulation of transcription by RNA polymerase II, positive regulation of neuroblast proliferation, regulation of transcription by RNA polymerase II, regulation of double-strand break repair via homologous recombination, positive regulation of epithelial to mesenchymal transition, positive regulation of protein ubiquitination.

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-11-30.

**Submitter consensus:** unanimous (3/3 Likely benign).

**Submission history:** 3 submissions (2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-30 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-04-20 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2024-07-01 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

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

## Similar variants {#similar}

Related KDM1A variant pages (same residue, condition, or type): [KDM1A p.Ala10Val](/variant/kdm1a-p-ala10val), [KDM1A p.Ala11Ser](/variant/kdm1a-p-ala11ser), [KDM1A p.Ala11Thr](/variant/kdm1a-p-ala11thr), [KDM1A p.Ala12Val](/variant/kdm1a-p-ala12val), [KDM1A p.Ala13Thr](/variant/kdm1a-p-ala13thr), [KDM1A p.Ala18Thr](/variant/kdm1a-p-ala18thr), [KDM1A p.Ala197Thr](/variant/kdm1a-p-ala197thr), [KDM1A p.Ala558Gly](/variant/kdm1a-p-ala558gly).

### 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 3257233). 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.*