# NM_021078.3(KAT2A):c.136C>G (p.Pro46Ala)

https://sugi.bio/variant/kat2a-p-pro46ala

## Summary

**KAT2A p.Pro46Ala (c.136C>G)** is classified **Uncertain significance** in KAT2A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-30). AlphaMissense: likely benign (0.0453); Very rare (popmax 9.34e-05%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · very rare (popmax 9.34e-05%, nfe)

## For patients & families {#patients}

This is a change in the KAT2A 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 | [KAT2A](https://sugi.bio/atlas/gene/KAT2A/) |
| Protein change (HGVS p.) | p.Pro46Ala |
| Coding change (HGVS c.) | c.136C>G |
| MANE Select transcript | [NM_021078](https://www.ncbi.nlm.nih.gov/nuccore/NM_021078) |
| Variant type | single nucleotide variant |
| Location | chr17:42121169-42121169 (GRCh38) |
| ClinVar | [VCV4089758](https://www.ncbi.nlm.nih.gov/clinvar/variation/4089758/) |

**All HGVS expressions:** `NC_000017.10:g.40273187G>C`, `NC_000017.11:g.42121169G>C`, `NG_196122.1:g.36G>C`, `NM_001376227.1:c.136C>G`, `NM_021078.3:c.136C>G`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.0453)
- REVEL 0.165 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -8.246 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 6.061, GERP -1.74, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 17.11**. 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.*
- Regional missense constraint: **o/e 1.15** across the covering region of the MANE Select transcript (42,121,052–42,121,304), spanning 252 bp. Chi-square p 0.09. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code 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 **9.34e-05%** (nfe) · 1/1,070,340 in the highest group · 1/1,419,896 alleles overall — very rare (popmax 9.34e-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}

**KAT2A** population constraint: LOEUF 0.587, pLI 0.0052234, missense-Z 3.8125. *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 **46** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 79.62, 56% of residues very-high.

**15 experimental structure(s)** (PDB): [10DW](https://www.rcsb.org/structure/10DW), [1F68](https://www.rcsb.org/structure/1F68), [1Z4R](https://www.rcsb.org/structure/1Z4R), [3D7C](https://www.rcsb.org/structure/3D7C), [5H84](https://www.rcsb.org/structure/5H84), [5H86](https://www.rcsb.org/structure/5H86).

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

*Describes the biological roles of KAT2A (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:** KAT2A's established molecular role includes chromatin binding. p.Pro46Ala falls in the disordered region. In Reactome, KAT2A is annotated in disease pathway(s) including **Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants**, **Constitutive Signaling by NOTCH1 PEST Domain Mutants**.

**Disease mechanism (Reactome):** KAT2A loss or alteration is curated in [Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants](https://reactome.org/content/detail/R-HSA-2894862), [Constitutive Signaling by NOTCH1 PEST Domain Mutants](https://reactome.org/content/detail/R-HSA-2644606).

### Pathways affected {#pathways}

KAT2A participates in **17 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants](https://reactome.org/content/detail/R-HSA-2894862) | curated |
| ⚕ [Constitutive Signaling by NOTCH1 PEST Domain Mutants](https://reactome.org/content/detail/R-HSA-2644606) | curated |
| [B-WICH complex positively regulates rRNA expression](https://reactome.org/content/detail/R-HSA-5250924) | curated |
| [Formation of WDR5-containing histone-modifying complexes](https://reactome.org/content/detail/R-HSA-9772755) | curated |
| [NOTCH4 Intracellular Domain Regulates Transcription](https://reactome.org/content/detail/R-HSA-9013695) | curated |
| [Notch-HLH transcription pathway](https://reactome.org/content/detail/R-HSA-350054) | curated |
| [Ub-specific processing proteases](https://reactome.org/content/detail/R-HSA-5689880) | curated |
| [Cardiogenesis](https://reactome.org/content/detail/R-HSA-9733709) | electronic |
| [Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)](https://reactome.org/content/detail/R-HSA-9976102) | electronic |
| [Formation of paraxial mesoderm](https://reactome.org/content/detail/R-HSA-9793380) | electronic |
| [HATs acetylate histones](https://reactome.org/content/detail/R-HSA-3214847) | electronic |
| [NOTCH1 Intracellular Domain Regulates Transcription](https://reactome.org/content/detail/R-HSA-2122947) | electronic |
| [NOTCH3 Intracellular Domain Regulates Transcription](https://reactome.org/content/detail/R-HSA-9013508) | electronic |
| [Pre-NOTCH Transcription and Translation](https://reactome.org/content/detail/R-HSA-1912408) | electronic |
| [RNA Polymerase I Transcription Initiation](https://reactome.org/content/detail/R-HSA-73762) | electronic |
| [RUNX3 regulates NOTCH signaling](https://reactome.org/content/detail/R-HSA-8941856) | electronic |
| [Regulation of gene expression in late stage (branching morphogenesis) pancreatic bud precursor cells](https://reactome.org/content/detail/R-HSA-210744) | electronic |

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

**Molecular function:** chromatin binding, transcription coactivator activity, histone acetyltransferase activity, histone H3 acetyltransferase activity, acetyltransferase activity, histone deacetylase binding.

**Biological process:** negative regulation of transcription by RNA polymerase II, regulation of DNA-templated transcription, regulation of transcription by RNA polymerase II, internal peptidyl-lysine acetylation, regulation of protein stability, negative regulation of gluconeogenesis.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-06-30.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-06-30 |

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

## Similar variants {#similar}

Related KAT2A variant pages (same residue, condition, or type): [KAT2A c.464-18C>G](/variant/kat2a-c-464-minus-18c-g), [KAT2A p.Leu664=](/variant/kat2a-p-leu664), [KAT2A p.Leu719=](/variant/kat2a-p-leu719), [KAT2A p.Ala274Val](/variant/kat2a-p-ala274val), [KAT2A p.Ala426Val](/variant/kat2a-p-ala426val), [KAT2A p.Ala53Ser](/variant/kat2a-p-ala53ser), [KAT2A p.Ala53Val](/variant/kat2a-p-ala53val), [KAT2A p.Arg171Gly](/variant/kat2a-p-arg171gly).

### 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 4089758). 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.*