# NM_003884.5(KAT2B):c.363C>A (p.Pro121=)

https://sugi.bio/variant/kat2b-p-pro121

## Summary

**KAT2B p.Pro121= (c.363C>A)** is classified **Likely benign** in KAT2B (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-07-01). Ultra-rare (popmax 0.0334%, eas); Associated with KAT2B-related disorder.

**At a glance:** Likely benign · review: No assertion criteria · rsID rs555906565 · 1 submitter · 1 linked condition · ultra-rare (popmax 0.0334%, eas)

## For patients & families {#patients}

This is a change in the KAT2B gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to KAT2B-related disorder.

*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 | [KAT2B](https://sugi.bio/atlas/gene/KAT2B/) |
| Protein change (HGVS p.) | p.Pro121= |
| Coding change (HGVS c.) | c.363C>A |
| MANE Select transcript | [NM_003884](https://www.ncbi.nlm.nih.gov/nuccore/NM_003884) |
| dbSNP | [rs555906565](https://www.ncbi.nlm.nih.gov/snp/rs555906565/) |
| Variant type | single nucleotide variant |
| Location | chr3:20072392-20072392 (GRCh38) |
| ClinVar | [VCV3042621](https://www.ncbi.nlm.nih.gov/clinvar/variation/3042621/) |

**All HGVS expressions:** `NC_000003.11:g.20113884C>A`, `NC_000003.12:g.20072392C>A`, `NM_003884.5:c.363C>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 (below), not from a missing predictor score.
- Conservation: phyloP -0.889, GERP -2.72, phastCons 0.001 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 7.206**. 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: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for KAT2B (1,204 scored positions, the nearest 8 bases away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency (gnomAD v4.1): grpmax **0.0334%** (eas) · FAF95 0.0206% · FAF99 0.0166% · 15/44,882 in the highest group · 50/1,613,416 alleles overall — ultra-rare (popmax 0.0334%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.0334% | 2,992 |
| South Asian | 0.0198% | 5,059 |
| Middle Eastern | 0.0165% | 6,062 |
| Admixed American | 0.00667% | 15,003 |
| Remaining individuals (not grpmax-eligible) | 0.0064% | 15,620 |
| European (non-Finnish) | 0.000678% | 147,417 |

*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}

**KAT2B** population constraint: LOEUF 0.461, pLI 0.9982, missense-Z 1.7615. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 78.22, 44% of residues very-high.

**25 experimental structure(s)** (PDB): [1CM0](https://www.rcsb.org/structure/1CM0), [1JM4](https://www.rcsb.org/structure/1JM4), [1N72](https://www.rcsb.org/structure/1N72), [1WUG](https://www.rcsb.org/structure/1WUG), [1WUM](https://www.rcsb.org/structure/1WUM), [1ZS5](https://www.rcsb.org/structure/1ZS5).

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

*Describes the biological roles of KAT2B (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:** KAT2B's established molecular role includes transcription coregulator activity. In Reactome, KAT2B 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):** KAT2B 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}

KAT2B participates in **21 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 |
| [Estrogen-dependent gene expression](https://reactome.org/content/detail/R-HSA-9018519) | curated |
| [Formation of WDR5-containing histone-modifying complexes](https://reactome.org/content/detail/R-HSA-9772755) | curated |
| [Metalloprotease DUBs](https://reactome.org/content/detail/R-HSA-5689901) | 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 |
| [Physiological factors](https://reactome.org/content/detail/R-HSA-5578768) | curated |
| [RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function](https://reactome.org/content/detail/R-HSA-8936459) | curated |
| [Regulation of FOXO transcriptional activity by acetylation](https://reactome.org/content/detail/R-HSA-9617629) | curated |
| [YAP1- and WWTR1 (TAZ)-stimulated gene expression](https://reactome.org/content/detail/R-HSA-2032785) | curated |
| [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:** transcription coregulator activity, transcription coactivator activity, histone acetyltransferase activity, L-lysine N6-acetyltransferase activity, acting on acetyl phosphate as donor, enzyme activator activity, acetyltransferase activity.

**Biological process:** negative regulation of transcription by RNA polymerase II, chromatin remodeling, protein acetylation, negative regulation of cell population proliferation, internal peptidyl-lysine acetylation, cellular response to insulin stimulus.

## Clinical significance {#significance}

**Likely benign** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2019-07-01.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2019-07-01 |

## Associated conditions {#conditions}

[KAT2B-related disorder](https://sugi.bio/atlas/disease/kat2b-related-disorder/).

**Reported phenotype names (ClinVar):** KAT2B-related disorder, KAT2B-related condition.

## Similar variants {#similar}

Related KAT2B variant pages (same residue, condition, or type): [KAT2B p.Pro121Arg](/variant/kat2b-p-pro121arg), [KAT2B p.Ile764Val](/variant/kat2b-p-ile764val), [KAT2B p.Ala466Val](/variant/kat2b-p-ala466val), [KAT2B p.Gly208Ala](/variant/kat2b-p-gly208ala), [KAT2B p.Ser434Cys](/variant/kat2b-p-ser434cys), [KAT2B c.2157-5T>C](/variant/kat2b-c-2157-minus-5t-c), [KAT2B c.670-3A>C](/variant/kat2b-c-670-minus-3a-c), [KAT2B c.852-5C>T](/variant/kat2b-c-852-minus-5c-t).

### 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 3042621). 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.*