# NM_006766.5(KAT6A):c.603G>A (p.Pro201=)

https://sugi.bio/variant/kat6a-p-pro201

## Summary

**KAT6A p.Pro201= (c.603G>A)** is classified **Benign/Likely benign** in KAT6A (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-11). Ultra-rare (popmax 0.0206%, nfe); Associated with Inborn genetic diseases.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs148925079 · 4 submitters · 1 linked condition · ultra-rare (popmax 0.0206%, nfe)

## For patients & families {#patients}

This is a change in the KAT6A gene that is classified as benign/likely benign — not considered disease-causing, submitted by 4 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 | [KAT6A](https://sugi.bio/atlas/gene/KAT6A/) |
| Protein change (HGVS p.) | p.Pro201= |
| Coding change (HGVS c.) | c.603G>A |
| MANE Select transcript | [NM_006766](https://www.ncbi.nlm.nih.gov/nuccore/NM_006766) |
| dbSNP | [rs148925079](https://www.ncbi.nlm.nih.gov/snp/rs148925079/) |
| Variant type | single nucleotide variant |
| Location | chr8:41987561-41987561 (GRCh38) |
| ClinVar | [VCV589173](https://www.ncbi.nlm.nih.gov/clinvar/variation/589173/) |

**All HGVS expressions:** `NC_000008.10:g.41845079C>T`, `NC_000008.11:g.41987561C>T`, `NG_042093.1:g.69466G>A`, `NM_001305878.2:c.603G>A`, `NM_006766.5:c.603G>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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor gain** (Δ 0.58) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -5.706, GERP -4.76 — fast-evolving / accelerated position
- CADD: **PHRED 17.16**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.58**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.58**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.0206%** (nfe) · FAF95 0.0184% · FAF99 0.0176% · 239/1,159,314 in the highest group · 269/1,590,080 alleles overall — ultra-rare (popmax 0.0206%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0259% | 3,857 |
| European (non-Finnish) (grpmax) | 0.0206% | 4,851 |
| Middle Eastern | 0.0166% | 6,042 |
| Finnish (not grpmax-eligible) | 0.00938% | 10,659 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.0034% | 29,408 |
| Admixed American | 0.00336% | 29,777 |
| African / African-American | 0.00269% | 37,115 |
| South Asian | 0.00222% | 45,090 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**KAT6A** population constraint: LOEUF 0.083, pLI 1, missense-Z 3.137; ClinGen dosage — haploinsufficiency 3/3, triplosensitivity 0/3. *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):

- **syndromic intellectual disability** — Definitive (AD)

## Protein context {#protein}

Residue **201** lies in the 'interaction with pml' region.

AlphaFold model confidence (whole protein): pLDDT 49.12, 17% of residues very-high.

**21 experimental structure(s)** (PDB): [1M36](https://www.rcsb.org/structure/1M36), [2LN0](https://www.rcsb.org/structure/2LN0), [2OZU](https://www.rcsb.org/structure/2OZU), [2RC4](https://www.rcsb.org/structure/2RC4), [3V43](https://www.rcsb.org/structure/3V43), [4LJN](https://www.rcsb.org/structure/4LJN) — incl. mutant structure 5B78.

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

*Describes the biological roles of KAT6A (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:** KAT6A's established molecular role includes DNA binding. p.Pro201= falls in the interaction with pml region.


### Pathways affected {#pathways}

KAT6A participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [HATs acetylate histones](https://reactome.org/content/detail/R-HSA-3214847) | curated |
| [Regulation of TP53 Activity through Acetylation](https://reactome.org/content/detail/R-HSA-6804758) | curated |

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

**Molecular function:** DNA binding, transcription coactivator activity, histone acetyltransferase activity, zinc ion binding, acetyltransferase activity, histone H3K14 acetyltransferase activity.

**Biological process:** regulation of DNA-templated transcription, myeloid cell differentiation, negative regulation of DNA-templated transcription, positive regulation of DNA-templated transcription, cellular senescence.

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-11.

**Submitter consensus:** conflicting (3 Likely benign, 1 Benign).

**Submission history:** 4 submissions (2017–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2019-09-18 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2017-05-27 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-01-11 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2023-11-01 |

## 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 KAT6A variant pages (same residue, condition, or type): [KAT6A p.Pro201Leu](/variant/kat6a-p-pro201leu), [KAT6A p.Arg1129Ter](/variant/kat6a-p-arg1129ter), [KAT6A p.Arg148Ter](/variant/kat6a-p-arg148ter), [KAT6A p.Arg286Ter](/variant/kat6a-p-arg286ter), [KAT6A p.Arg735Ter](/variant/kat6a-p-arg735ter), [KAT6A p.Ala1451Gly](/variant/kat6a-p-ala1451gly), [KAT6A p.Ala492Val](/variant/kat6a-p-ala492val), [KAT6A p.Arg1086Ser](/variant/kat6a-p-arg1086ser).

### 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 589173). 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.*