# NM_004656.4(BAP1):c.1026C>T (p.Ser342=)

https://sugi.bio/variant/bap1-p-ser342

## Summary

**BAP1 p.Ser342= (c.1026C>T)** is classified **Benign/Likely benign** in BAP1 (ClinVar, Multiple submitters, 25 submitters; last evaluated 2026-06-01). Rare (popmax 0.467%, nfe); Associated with Kury-Isidor syndrome.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs71651686 · 25 submitters · 4 linked conditions · rare (popmax 0.467%, nfe)

## For patients & families {#patients}

This is a change in the BAP1 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 25 submitters, and is linked to Kury-Isidor syndrome.

*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 | [BAP1](https://sugi.bio/atlas/gene/BAP1/) |
| Protein change (HGVS p.) | p.Ser342= |
| Coding change (HGVS c.) | c.1026C>T |
| MANE Select transcript | [NM_004656](https://www.ncbi.nlm.nih.gov/nuccore/NM_004656) |
| dbSNP | [rs71651686](https://www.ncbi.nlm.nih.gov/snp/rs71651686/) |
| Variant type | single nucleotide variant |
| Location | chr3:52405200-52405200 (GRCh38) |
| ClinVar | [VCV220780](https://www.ncbi.nlm.nih.gov/clinvar/variation/220780/) |

**All HGVS expressions:** `LRG_529:g.9794C>T`, `LRG_529t1:c.1026C>T`, `NC_000003.11:g.52439216G>A`, `NC_000003.12:g.52405200G>A`, `NG_031859.1:g.9794C>T`, `NM_004656.4:c.1026C>T`

## 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 4.046, GERP 1.75, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 7.319**. 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: **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 **0.467%** (nfe) · FAF95 0.456% · FAF99 0.452% · 5,509/1,180,036 in the highest group · 6,244/1,614,102 alleles overall — rare (popmax 0.467%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Ashkenazi Jewish (not grpmax-eligible) | 0.628% | 159 |
| European (non-Finnish) (grpmax) | 0.467% | 214 |
| Admixed American | 0.386% | 259 |
| Remaining individuals (not grpmax-eligible) | 0.355% | 282 |
| African / African-American | 0.0879% | 1,137 |
| Middle Eastern | 0.0825% | 1,212 |
| Finnish (not grpmax-eligible) | 0.0172% | 5,812 |
| South Asian | 0.0143% | 7,007 |

Ashkenazi Jewish 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}

**BAP1** population constraint: LOEUF 0.324, pLI 1, missense-Z 3.277. *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):

- **BAP1-related tumor predisposition syndrome** — Definitive (AD)

## Protein context {#protein}

Residue **342** lies in the 'disordered' region; a UniProt-annotated variant site (in tpds1).

AlphaFold model confidence (whole protein): pLDDT 63.87, 32% of residues very-high.

**4 experimental structure(s)** (PDB): [7VPW](https://www.rcsb.org/structure/7VPW), [8H1T](https://www.rcsb.org/structure/8H1T), [8SVF](https://www.rcsb.org/structure/8SVF), [9U5U](https://www.rcsb.org/structure/9U5U).

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

*Describes the biological roles of BAP1 (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:** BAP1's established molecular role includes chromatin binding. p.Ser342= falls in the disordered region.


### Pathways affected {#pathways}

BAP1 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks](https://reactome.org/content/detail/R-HSA-5693565) | curated |
| [UCH proteinases](https://reactome.org/content/detail/R-HSA-5689603) | curated |

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

**Molecular function:** chromatin binding, cysteine-type deubiquitinase activity, histone H2A deubiquitinase activity.

**Biological process:** regulation of cell growth, protein deubiquitination, monoubiquitinated protein deubiquitination, negative regulation of DNA-templated transcription, regulation of cell cycle, protein K48-linked deubiquitination.

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-06-01.

**Submitter consensus:** conflicting (14 Likely benign, 11 Benign, 1 benign).

**Submission history:** 26 submissions (2016–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Benign | criteria provided, single submitter | clinical testing |  |
| True Health Diagnostics | Likely benign | no assertion criteria provided | clinical testing | 2018-06-05 |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | Likely benign | no assertion criteria provided | clinical testing |  |
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Likely benign | no assertion criteria provided | clinical testing |  |
| Genetic Services Laboratory, University of Chicago | Benign | criteria provided, single submitter | clinical testing | 2019-06-19 |
| Color Diagnostics, LLC DBA Color Health | Likely benign | criteria provided, single submitter | clinical testing | 2016-03-09 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2016-11-10 |
| Department of Pathology and Laboratory Medicine, Sinai Health System | Benign | criteria provided, single submitter | clinical testing | 2023-06-16 |
| Mayo Clinic Laboratories, Mayo Clinic | Likely benign | criteria provided, single submitter | clinical testing | 2025-07-23 |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Benign | criteria provided, single submitter | clinical testing | 2025-06-17 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-04 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-22 |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2018-01-19 |
| Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | Likely benign | no assertion criteria provided | clinical testing |  |
| Genome Diagnostics Laboratory, Amsterdam University Medical Center | Likely benign | no assertion criteria provided | clinical testing |  |
| Genome Diagnostics Laboratory, University Medical Center Utrecht | Benign | no assertion criteria provided | clinical testing |  |
| Sema4, Sema4 | Benign | criteria provided, single submitter | curation | 2020-10-22 |
| Fulgent Genetics, Fulgent Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2021-07-14 |
| KCCC/NGS Laboratory, Kuwait Cancer Control Center | Benign | criteria provided, single submitter | clinical testing | 2023-07-07 |
| Breakthrough Genomics, Breakthrough Genomics | Likely benign | criteria provided, single submitter | not provided |  |
| Myriad Genetics, Inc. | Benign | criteria provided, single submitter | clinical testing | 2024-07-15 |
| Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Likely benign | criteria provided, single submitter | clinical testing | 2025-03-04 |
| KCCC/NGS Laboratory, Kuwait Cancer Control Center | Benign | criteria provided, single submitter | clinical testing | 2025-02-01 |
| Quest Diagnostics Nichols Institute San Juan Capistrano | benign | criteria provided, single submitter | clinical testing | 2025-08-04 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2026-06-01 |

## Associated conditions {#conditions}

[Kury-Isidor syndrome](https://sugi.bio/atlas/disease/kury-isidor-syndrome/), [melanoma, uveal, susceptibility to, 2](https://sugi.bio/atlas/disease/melanoma-uveal-susceptibility-to-2/), [BAP1-related tumor predisposition syndrome](https://sugi.bio/atlas/disease/bap1-related-tumor-predisposition-syndrome/), [hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/).

**Reported phenotype names (ClinVar):** Kury-Isidor syndrome, BAP1-related tumor predisposition syndrome, not specified, Hereditary cancer-predisposing syndrome, not provided, Melanoma, uveal, susceptibility to, 2, COMMON Syndrome, Tumor susceptibility linked to germline BAP1 mutations, BAP1 tumor predisposition syndrome, TUMOR PREDISPOSITION SYNDROME 1.

## Similar variants {#similar}

Related BAP1 variant pages (same residue, condition, or type): [BAP1 p.Ser342Ile](/variant/bap1-p-ser342ile), [BAP1 p.Ser342Gly](/variant/bap1-p-ser342gly), [BAP1 p.Ser342Thr](/variant/bap1-p-ser342thr), [BAP1 c.1117-1G>A](/variant/bap1-c-1117-minus-1g-a), [BAP1 c.122+1G>A](/variant/bap1-c-122-plus-1g-a), [BAP1 c.122+1G>T](/variant/bap1-c-122-plus-1g-t), [BAP1 c.122+5G>A](/variant/bap1-c-122-plus-5g-a), [BAP1 c.122+5G>C](/variant/bap1-c-122-plus-5g-c).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2026-07-14); 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 220780). 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.*