# NM_012330.4(KAT6B):c.5862_5867delinsCTGCATTTGGGAAAATA (p.Pro1955fs)

https://sugi.bio/variant/kat6b-p-pro1955fs

## Summary

**KAT6B p.Pro1955fs (c.5862_5867delinsCTGCATTTGGGAAAATA)** is classified **Uncertain significance** in KAT6B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-30). Associated with blepharophimosis - intellectual disability syndrome, SBBYS type.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition

## For patients & families {#patients}

This is a change in the KAT6B gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to blepharophimosis - intellectual disability syndrome, SBBYS type.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0016618/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [KAT6B](https://sugi.bio/atlas/gene/KAT6B/) |
| Protein change (HGVS p.) | p.Pro1955fs |
| Coding change (HGVS c.) | c.5862_5867delinsCTGCATTTGGGAAAATA |
| MANE Select transcript | [NM_012330](https://www.ncbi.nlm.nih.gov/nuccore/NM_012330) |
| Variant type | Indel |
| Location | chr10:75030686-75030691 (GRCh38) |
| ClinVar | [VCV4855796](https://www.ncbi.nlm.nih.gov/clinvar/variation/4855796/) |

**All HGVS expressions:** `NC_000010.10:g.76790444_76790449delinsCTGCATTTGGGAAAATA`, `NC_000010.11:g.75030686_75030691delinsCTGCATTTGGGAAAATA`, `NG_032048.1:g.209274_209279delinsCTGCATTTGGGAAAATA`, `NG_119859.1:g.662_667delinsCTGCATTTGGGAAAATA`, `NM_001256468.2:c.5313_5318delinsCTGCATTTGGGAAAATA`, `NM_001256469.2:c.4986_4991delinsCTGCATTTGGGAAAATA`, `NM_001370132.1:c.4824_4829delinsCTGCATTTGGGAAAATA`, `NM_001370133.1:c.4173_4178delinsCTGCATTTGGGAAAATA`, `NM_001370134.1:c.3777_3782delinsCTGCATTTGGGAAAATA`, `NM_001370135.1:c.3519_3524delinsCTGCATTTGGGAAAATA`, `NM_001370136.1:c.5862_5867delinsCTGCATTTGGGAAAATA`, `NM_001370137.1:c.5862_5867delinsCTGCATTTGGGAAAATA`, `NM_001370138.1:c.5313_5318delinsCTGCATTTGGGAAAATA`, `NM_001370139.1:c.4986_4991delinsCTGCATTTGGGAAAATA`, `NM_001370140.1:c.4986_4991delinsCTGCATTTGGGAAAATA`, `NM_001370141.1:c.4986_4991delinsCTGCATTTGGGAAAATA`, `NM_001370142.1:c.4986_4991delinsCTGCATTTGGGAAAATA`, `NM_001370143.1:c.4797_4802delinsCTGCATTTGGGAAAATA`, `NM_001370144.1:c.4797_4802delinsCTGCATTTGGGAAAATA`, `NM_012330.4:c.5862_5867delinsCTGCATTTGGGAAAATA`

## 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 0.313, GERP 0.861, phastCons 0.997 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene (constraint LOEUF 0.098, pLI 1), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in the last exon (18 of 18)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no indel variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.

*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}

**KAT6B** population constraint: LOEUF 0.098, pLI 1, missense-Z 4.8917; 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):

- **KAT6B-related multiple congenital anomalies syndrome** — Definitive (AD)
- **RASopathy** — Disputed (AD)

## Protein context {#protein}

Residue **1955** lies in the 'interaction with runx1 and runx2' region.

AlphaFold model confidence (whole protein): pLDDT 49.67, 17% of residues very-high.

**3 experimental structure(s)** (PDB): [5U2J](https://www.rcsb.org/structure/5U2J), [6OIE](https://www.rcsb.org/structure/6OIE), [8E4V](https://www.rcsb.org/structure/8E4V).

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

*Describes the biological roles of KAT6B (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:** KAT6B's established molecular role includes transcription coactivator activity. p.Pro1955fs falls in the interaction with runx1 and runx2 region.


### Pathways affected {#pathways}

KAT6B 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:** transcription coactivator activity, histone acetyltransferase activity, histone H3K14 acetyltransferase activity, protein-lysine-acetyltransferase activity.

**Biological process:** regulation of DNA-templated transcription, negative regulation of DNA-templated transcription, positive regulation of DNA-templated transcription.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-07-30.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| 3billion | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-07-30 |

## Associated conditions {#conditions}

[blepharophimosis - intellectual disability syndrome, SBBYS type](https://sugi.bio/atlas/disease/blepharophimosis-intellectual-disability-syndrome-sbbys-type/).

**Reported phenotype names (ClinVar):** Blepharophimosis - intellectual disability syndrome, SBBYS type, Say-Barber-Biesecker variant of Ohdo syndrome (SBBYSS), Young Simpson syndrome, Mental retardation unusual facies hypothyroidism, Ohdo syndrome, SBBYS variant, SBBYSS syndrome, Say-Barber-Biesecker-Young-Simpson syndrome, Say-Barber-Biesecker-Young-Simpson variant of Ohdo Syndrome, Say-Barber-Biesecker Variant of Ohdo Syndrome.

## Similar variants {#similar}

Related KAT6B variant pages (same residue, condition, or type): [KAT6B p.Pro1955Ala](/variant/kat6b-p-pro1955ala), [KAT6B p.Ala1120_Ile1121insTer](/variant/kat6b-p-ala1120-ile1121inster), [KAT6B p.His1433fs](/variant/kat6b-p-his1433fs), [KAT6B p.Met1690fs](/variant/kat6b-p-met1690fs), [KAT6B c.3664+1G>A](/variant/kat6b-c-3664-plus-1g-a), [KAT6B p.Arg1058Ter](/variant/kat6b-p-arg1058ter), [KAT6B p.Arg1797Ter](/variant/kat6b-p-arg1797ter), [KAT6B p.Arg783Ter](/variant/kat6b-p-arg783ter).

### 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 4855796). 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.*