# NM_182710.3(KAT5):c.477C>T (p.Pro159=)

https://sugi.bio/variant/kat5-p-pro159

## Summary

**KAT5 p.Pro159= (c.477C>T)** is classified **Likely benign** in KAT5 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-20). Very rare (popmax 0.0011%, sas).

**At a glance:** Likely benign · review: Single submitter · 1 submitter · very rare (popmax 0.0011%, sas)

## For patients & families {#patients}

This is a change in the KAT5 gene that is classified as likely benign — not considered disease-causing, 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 | [KAT5](https://sugi.bio/atlas/gene/KAT5/) |
| Protein change (HGVS p.) | p.Pro159= |
| Coding change (HGVS c.) | c.477C>T |
| MANE Select transcript | [NM_182710](https://www.ncbi.nlm.nih.gov/nuccore/NM_182710) |
| Variant type | single nucleotide variant |
| Location | chr11:65713440-65713440 (GRCh38) |
| ClinVar | [VCV4912320](https://www.ncbi.nlm.nih.gov/clinvar/variation/4912320/) |

**All HGVS expressions:** `LRG_280:g.12499G>A`, `NC_000011.10:g.65713440C>T`, `NC_000011.9:g.65480911C>T`, `NG_008976.2:g.12499G>A`, `NG_033057.1:g.6439C>T`, `NM_001206833.2:c.385-153C>T`, `NM_006388.4:c.378C>T`, `NM_182709.3:c.286-153C>T`, `NM_182710.3:c.477C>T`

## 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 3.301, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 15.82**. 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: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.39 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0011%** (sas) · FAF95 6.8e-05% · FAF99 1.9e-05% · 1/91,078 in the highest group · 4/1,614,170 alleles overall — very rare (popmax 0.0011%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.0011% | 91,078 |
| European (non-Finnish) | 0.000254% | 393,340 |

*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}

**KAT5** population constraint: LOEUF 0.594, pLI 0.027252, missense-Z 3.7481. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **159** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 76.76, 50% of residues very-high.

**3 experimental structure(s)** (PDB): [2EKO](https://www.rcsb.org/structure/2EKO), [2OU2](https://www.rcsb.org/structure/2OU2), [4QQG](https://www.rcsb.org/structure/4QQG).

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

*Describes the biological roles of KAT5 (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:** KAT5's established molecular role includes chromatin binding. p.Pro159= falls in the disordered region. In Reactome, KAT5 is annotated in disease pathway(s) including **Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function**, **Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function**.

**Disease mechanism (Reactome):** KAT5 loss or alteration is curated in [Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function](https://reactome.org/content/detail/R-HSA-9704331), [Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function](https://reactome.org/content/detail/R-HSA-9704646), [Defective homologous recombination repair (HRR) due to BRCA1 loss of function](https://reactome.org/content/detail/R-HSA-9701192).

### Pathways affected {#pathways}

KAT5 participates in **22 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function](https://reactome.org/content/detail/R-HSA-9704331) | curated |
| ⚕ [Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function](https://reactome.org/content/detail/R-HSA-9704646) | curated |
| ⚕ [Defective homologous recombination repair (HRR) due to BRCA1 loss of function](https://reactome.org/content/detail/R-HSA-9701192) | curated |
| ⚕ [Impaired BRCA2 binding to PALB2](https://reactome.org/content/detail/R-HSA-9709603) | curated |
| ⚕ [Impaired BRCA2 binding to RAD51](https://reactome.org/content/detail/R-HSA-9709570) | curated |
| [DNA Damage/Telomere Stress Induced Senescence](https://reactome.org/content/detail/R-HSA-2559586) | curated |
| [Estrogen-dependent gene expression](https://reactome.org/content/detail/R-HSA-9018519) | curated |
| [G2/M DNA damage checkpoint](https://reactome.org/content/detail/R-HSA-69473) | curated |
| [HDR through Homologous Recombination (HRR)](https://reactome.org/content/detail/R-HSA-5685942) | curated |
| [HDR through Single Strand Annealing (SSA)](https://reactome.org/content/detail/R-HSA-5685938) | curated |
| [Homologous DNA Pairing and Strand Exchange](https://reactome.org/content/detail/R-HSA-5693579) | curated |
| [Nonhomologous End-Joining (NHEJ)](https://reactome.org/content/detail/R-HSA-5693571) | curated |
| [Presynaptic phase of homologous DNA pairing and strand exchange](https://reactome.org/content/detail/R-HSA-5693616) | curated |
| [Processing of DNA double-strand break ends](https://reactome.org/content/detail/R-HSA-5693607) | curated |
| [Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks](https://reactome.org/content/detail/R-HSA-5693565) | curated |
| [Regulation of TP53 Activity through Phosphorylation](https://reactome.org/content/detail/R-HSA-6804756) | curated |
| [Resolution of D-loop Structures through Holliday Junction Intermediates](https://reactome.org/content/detail/R-HSA-5693568) | curated |
| [Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)](https://reactome.org/content/detail/R-HSA-5693554) | curated |
| [Sensing of DNA Double Strand Breaks](https://reactome.org/content/detail/R-HSA-5693548) | curated |
| [Cardiogenesis](https://reactome.org/content/detail/R-HSA-9733709) | electronic |
| [Formation of the beta-catenin:TCF transactivating complex](https://reactome.org/content/detail/R-HSA-201722) | electronic |
| [HATs acetylate histones](https://reactome.org/content/detail/R-HSA-3214847) | electronic |

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

**Molecular function:** chromatin binding, transcription coactivator activity, histone acetyltransferase activity, histone H4 acetyltransferase activity, histone H2A acetyltransferase activity, histone H2AK5 acetyltransferase activity.

**Biological process:** negative regulation of transcription by RNA polymerase II, establishment of mitotic spindle orientation, double-strand break repair via homologous recombination, nucleotide-excision repair, double-strand break repair, DNA damage response.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-01-20.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2023-01-20 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related KAT5 variant pages (same residue, condition, or type): [KAT5 p.Pro159Leu](/variant/kat5-p-pro159leu), [KAT5 p.Cys308Ser](/variant/kat5-p-cys308ser), [KAT5 p.Gln310His](/variant/kat5-p-gln310his), [KAT5 p.Ser223Leu](/variant/kat5-p-ser223leu), [KAT5 p.Thr180Met](/variant/kat5-p-thr180met), [KAT5 p.Val32Asp](/variant/kat5-p-val32asp), [KAT5 p.Gly43=](/variant/kat5-p-gly43), [KAT5 p.Ser66=](/variant/kat5-p-ser66).

### 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 4912320). 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.*