# NM_001123385.2(BCOR):c.4822C>A (p.Pro1608Thr)

https://sugi.bio/variant/bcor-p-pro1608thr

## Summary

**BCOR p.Pro1608Thr (c.4822C>A)** is classified **Uncertain significance** in BCOR (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-14). AlphaMissense: likely benign (0.2026); Very rare (popmax 0.00693%, nfe); Associated with microphthalmia, syndromic 2.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs763713052 · 2 submitters · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.00693%, nfe)

## For patients & families {#patients}

This is a change in the BCOR gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, and is linked to microphthalmia, syndromic 2.

*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/0004628/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [BCOR](https://sugi.bio/atlas/gene/BCOR/) |
| Protein change (HGVS p.) | p.Pro1608Thr |
| Coding change (HGVS c.) | c.4822C>A |
| MANE Select transcript | [NM_001123385](https://www.ncbi.nlm.nih.gov/nuccore/NM_001123385) |
| dbSNP | [rs763713052](https://www.ncbi.nlm.nih.gov/snp/rs763713052/) |
| Variant type | single nucleotide variant |
| Location | chrX:40054040-40054040 (GRCh38) |
| ClinVar | [VCV2239921](https://www.ncbi.nlm.nih.gov/clinvar/variation/2239921/) |

**All HGVS expressions:** `LRG_627:g.128290C>A`, `LRG_627t1:c.4720C>A`, `LRG_627t2:c.4822C>A`, `NC_000023.10:g.39913293G>T`, `NC_000023.11:g.40054040G>T`, `NG_008880.1:g.128290C>A`, `NM_001123383.2:c.4720C>A`, `NM_001123384.2:c.4666C>A`, `NM_001123385.2:c.4822C>A`, `NM_017745.6:c.4720C>A`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.2026)
- REVEL 0.2 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -5.834 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **acceptor gain** (Δ 0.23) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 8.531, GERP 0.615, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 25.7**. 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 0.91** across the covering region of the MANE Select transcript (40,052,112–40,055,420), spanning 3,308 bp. Chi-square p 0.29. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.23**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.23**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.00693%** (nfe) · FAF95 0.00551% · FAF99 0.005% · 62/894,854 in the highest group · 66/1,097,113 alleles overall — very rare (popmax 0.00693%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00693% | 14,433 |
| Remaining individuals (not grpmax-eligible) | 0.0063% | 15,875 |
| Finnish (not grpmax-eligible) | 0.00214% | 46,833 |

*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}

**BCOR** population constraint: ClinGen dosage — haploinsufficiency 3, triplosensitivity 0 (0–3 scale). *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):

- **microphthalmia, syndromic 2** — Definitive (XL)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 39.82, 7% of residues very-high.

**5 experimental structure(s)** (PDB): [2N1L](https://www.rcsb.org/structure/2N1L), [3BIM](https://www.rcsb.org/structure/3BIM), [4HPL](https://www.rcsb.org/structure/4HPL), [6B7G](https://www.rcsb.org/structure/6B7G), [8HCU](https://www.rcsb.org/structure/8HCU).

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

*Describes the biological roles of BCOR (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:** BCOR's established molecular role includes transcription cis-regulatory region binding.


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

**Molecular function:** transcription cis-regulatory region binding, transcription corepressor activity, heat shock protein binding, histone deacetylase binding, DNA-binding transcription factor binding.

**Biological process:** negative regulation of transcription by RNA polymerase II, chromatin remodeling, heart development, negative regulation of bone mineralization, odontogenesis, negative regulation of DNA-templated transcription.

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-04-14.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2021–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-08-02 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-04-14 |

## Associated conditions {#conditions}

[microphthalmia, syndromic 2](https://sugi.bio/atlas/disease/microphthalmia-syndromic-2/).

**Reported phenotype names (ClinVar):** Oculofaciocardiodental syndrome, Inborn genetic diseases.

## Similar variants {#similar}

Related BCOR variant pages (same residue, condition, or type): [BCOR p.Pro1608=](/variant/bcor-p-pro1608), [BCOR p.Arg1163Ter](/variant/bcor-p-arg1163ter), [BCOR p.Arg1217Ter](/variant/bcor-p-arg1217ter), [BCOR p.Arg1514Ter](/variant/bcor-p-arg1514ter), [BCOR p.Arg342Ter](/variant/bcor-p-arg342ter), [BCOR p.Arg976Ter](/variant/bcor-p-arg976ter), [BCOR p.Ala1262Ser](/variant/bcor-p-ala1262ser), [BCOR p.Ala1307Pro](/variant/bcor-p-ala1307pro).

### 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 2239921). 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.*