# NM_007067.5(KAT7):c.17G>C (p.Arg6Thr)

https://sugi.bio/variant/kat7-p-arg6thr

## Summary

**KAT7 p.Arg6Thr (c.17G>C)** is classified **Uncertain significance** in KAT7 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-02). AlphaMissense: likely pathogenic (0.8316); Very rare (popmax 0.000932%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely pathogenic · very rare (popmax 0.000932%, nfe)

## For patients & families {#patients}

This is a change in the KAT7 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 | [KAT7](https://sugi.bio/atlas/gene/KAT7/) |
| Protein change (HGVS p.) | p.Arg6Thr |
| Coding change (HGVS c.) | c.17G>C |
| MANE Select transcript | [NM_007067](https://www.ncbi.nlm.nih.gov/nuccore/NM_007067) |
| Variant type | single nucleotide variant |
| Location | chr17:49791887-49791887 (GRCh38) |
| ClinVar | [VCV4680691](https://www.ncbi.nlm.nih.gov/clinvar/variation/4680691/) |

**All HGVS expressions:** `NC_000017.10:g.47869249G>C`, `NC_000017.11:g.49791887G>C`, `NG_051976.1:g.8269G>C`, `NG_051976.2:g.8208G>C`, `NM_001199155.2:c.17G>C`, `NM_001199156.2:c.17G>C`, `NM_001199157.2:c.17G>C`, `NM_001199158.2:c.17G>C`, `NM_001346706.2:c.17G>C`, `NM_007067.5:c.17G>C`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely pathogenic** (0.8316)
- REVEL 0.393 (indeterminate)
- SaProt LLR -8.502 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate
- Conservation: phyloP 11.859, GERP 1.64, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 28.8**. 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 0.70** across the covering region of the MANE Select transcript (49,788,835–49,798,511), spanning 9,676 bp. Chi-square p 6e-06. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>A, Δ0.25 acceptor 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 **0.000932%** (nfe) · FAF95 0.0005% · FAF99 0.000366% · 11/1,179,842 in the highest group · 11/1,613,936 alleles overall — very rare (popmax 0.000932%, 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}

**KAT7** population constraint: LOEUF 0.275, pLI 1, missense-Z 4.3936. *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 **6** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 73.21, 41% of residues very-high.

**8 experimental structure(s)** (PDB): [5GK9](https://www.rcsb.org/structure/5GK9), [6MAJ](https://www.rcsb.org/structure/6MAJ), [6MAK](https://www.rcsb.org/structure/6MAK), [7D0O](https://www.rcsb.org/structure/7D0O), [7D0P](https://www.rcsb.org/structure/7D0P), [7D0Q](https://www.rcsb.org/structure/7D0Q).

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

*Describes the biological roles of KAT7 (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:** KAT7's established molecular role includes DNA replication origin binding. p.Arg6Thr falls in the disordered region.


### Pathways affected {#pathways}

KAT7 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [HATs acetylate histones](https://reactome.org/content/detail/R-HSA-3214847) | curated |

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

**Molecular function:** DNA replication origin binding, histone acetyltransferase activity, histone H4 acetyltransferase activity, histone H3K14 acetyltransferase activity, histone H3K23 acetyltransferase activity, histone H4K5 acetyltransferase activity.

**Biological process:** regulation of cell growth, regulation of DNA replication, regulation of DNA-templated transcription, internal peptidyl-lysine acetylation, regulation of DNA-templated DNA replication initiation, stress-activated protein kinase signaling cascade.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-12-02.

**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 | 2025-12-02 |

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

## Similar variants {#similar}

Related KAT7 variant pages (same residue, condition, or type): [KAT7 p.Ala449=](/variant/kat7-p-ala449), [KAT7 c.580+1G>A](/variant/kat7-c-580-plus-1g-a), [KAT7 p.Ala133Val](/variant/kat7-p-ala133val), [KAT7 p.Ala154Thr](/variant/kat7-p-ala154thr), [KAT7 p.Ala40Thr](/variant/kat7-p-ala40thr), [KAT7 p.Ala8Val](/variant/kat7-p-ala8val), [KAT7 p.Arg344Leu](/variant/kat7-p-arg344leu), [KAT7 p.Arg37Gln](/variant/kat7-p-arg37gln).

### 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 4680691). 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.*