# NM_001123385.2(BCOR):c.2035G>A (p.Val679Ile)

https://sugi.bio/variant/bcor-p-val679ile

## Summary

**BCOR p.Val679Ile (c.2035G>A)** is classified **Conflicting classifications of pathogenicity** in BCOR (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2025-12-21). AlphaMissense: likely benign (0.1725); Rare (popmax 0.115%, mid); Associated with microphthalmia, syndromic 1.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs144722432 · 8 submitters · 2 linked conditions · AlphaMissense likely benign · rare (popmax 0.115%, mid)

## For patients & families {#patients}

This is a change in the BCOR gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 8 submitters, and is linked to microphthalmia, syndromic 1.

*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/0015304/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.Val679Ile |
| Coding change (HGVS c.) | c.2035G>A |
| MANE Select transcript | [NM_001123385](https://www.ncbi.nlm.nih.gov/nuccore/NM_001123385) |
| dbSNP | [rs144722432](https://www.ncbi.nlm.nih.gov/snp/rs144722432/) |
| Variant type | single nucleotide variant |
| Location | chrX:40073311-40073311 (GRCh38) |
| ClinVar | [VCV210518](https://www.ncbi.nlm.nih.gov/clinvar/variation/210518/) |

**All HGVS expressions:** `LRG_627:g.109019G>A`, `LRG_627t1:c.2035G>A`, `LRG_627t2:c.2035G>A`, `NC_000023.10:g.39932564C>T`, `NC_000023.11:g.40073311C>T`, `NG_008880.1:g.109019G>A`, `NM_001123383.2:c.2035G>A`, `NM_001123384.2:c.2035G>A`, `NM_001123385.2:c.2035G>A`, `NM_017745.6:c.2035G>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1725)
- REVEL 0.097 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.899 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 4.091, GERP 1.56, phastCons 0.999 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 22.6**. 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 0.90** across the covering region of the MANE Select transcript (40,072,481–40,074,597), spanning 2,116 bp. Chi-square p 0.013. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code 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 **0.115%** (mid) · FAF95 0.0957% · FAF99 0.0936% · 5/4,350 in the highest group · 1,002/1,208,652 alleles overall — rare (popmax 0.115%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.115% | 870 |
| European (non-Finnish) | 0.101% | 988 |
| Admixed American | 0.0944% | 1,060 |
| Remaining individuals (not grpmax-eligible) | 0.0547% | 1,829 |
| Finnish (not grpmax-eligible) | 0.03% | 3,333 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.0136% | 7,329 |
| African / African-American | 0.0104% | 9,590 |

*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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-12-21.

**Submitter consensus:** conflicting (5 Likely benign, 1 Uncertain significance, 1 Likely pathogenic, 1 Benign).

**Submission history:** 8 submissions (2014–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genetic Services Laboratory, University of Chicago | Uncertain significance | criteria provided, single submitter | clinical testing | 2014-08-08 |
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Likely benign | no assertion criteria provided | clinical testing |  |
| Eurofins Ntd Llc (ga) | Likely benign | criteria provided, single submitter | clinical testing | 2015-11-18 |
| Genomic Research Center, Shahid Beheshti University of Medical Sciences | Likely pathogenic | criteria provided, single submitter | clinical testing | 2017-12-03 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2025-12-21 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-20 |
| Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | Likely benign | no assertion criteria provided | clinical testing |  |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2021-01-22 |

## Associated conditions {#conditions}

[microphthalmia, syndromic 1](https://sugi.bio/atlas/disease/microphthalmia-syndromic-1/), [microphthalmia, syndromic 2](https://sugi.bio/atlas/disease/microphthalmia-syndromic-2/).

**Reported phenotype names (ClinVar):** Microphthalmia, syndromic 1, not specified, Oculofaciocardiodental syndrome, not provided, BCOR-related disorder, BCOR-related disorders, BCOR-related condition, AllHighlyPenetrant, none provided, ANOP1.

## Similar variants {#similar}

Related BCOR variant pages (same residue, condition, or type): [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), [BCOR p.Ala165Pro](/variant/bcor-p-ala165pro).

### 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 210518). 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.*