# NM_000465.4(BARD1):c.281A>C (p.Asp94Ala)

https://sugi.bio/variant/bard1-p-asp94ala

## Summary

**BARD1 p.Asp94Ala (c.281A>C)** is classified **Uncertain significance** in BARD1 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-31). AlphaMissense: likely pathogenic (0.8856); Ultra-rare (popmax 0.0167%, amr); Associated with hereditary breast carcinoma.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs757569689 · 6 submitters · 2 linked conditions · AlphaMissense likely pathogenic · ultra-rare (popmax 0.0167%, amr)

## For patients & families {#patients}

This is a change in the BARD1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 6 submitters, and is linked to hereditary breast carcinoma.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant, Multigenic/multifactorial |
| Age of onset (of this condition) | Adult, Elderly |
| Clinical trials | 10 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | BARD1 is a diagnostic-grade gene on 2 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017142/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [BARD1](https://sugi.bio/atlas/gene/BARD1/) |
| Protein change (HGVS p.) | p.Asp94Ala |
| Coding change (HGVS c.) | c.281A>C |
| MANE Select transcript | [NM_000465](https://www.ncbi.nlm.nih.gov/nuccore/NM_000465) |
| dbSNP | [rs757569689](https://www.ncbi.nlm.nih.gov/snp/rs757569689/) |
| Variant type | single nucleotide variant |
| Location | chr2:214792380-214792380 (GRCh38) |
| ClinVar | [VCV230637](https://www.ncbi.nlm.nih.gov/clinvar/variation/230637/) |

**All HGVS expressions:** `LRG_297:g.22332A>C`, `LRG_297t1:c.281A>C`, `NC_000002.11:g.215657104T>G`, `NC_000002.12:g.214792380T>G`, `NG_012047.3:g.22332A>C`, `NM_000465.4:c.281A>C`, `NM_001282543.2:c.224A>C`, `NM_001282545.2:c.215+4681A>C`, `NM_001282548.2:c.158+17032A>C`, `NM_001282549.2:c.281A>C`, `NR_104216.2:n.395A>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.8856)
- REVEL 0.696 (pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -8.434 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense and REVEL call this damaging; SaProt does not
- Conservation: phyloP 7.905, GERP 1.98, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 8%** most-pathogenic-predicted substitutions in BARD1 (of 4,555 modeled).
- CADD: **PHRED 24.9**. 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 1.06** across the covering region of the MANE Select transcript (214,728,679–214,809,569), spanning 80,890 bp. Chi-square p 0.077. 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 **0.0167%** (amr) · FAF95 0.00902% · FAF99 0.00683% · 10/59,860 in the highest group · 14/1,612,886 alleles overall — ultra-rare (popmax 0.0167%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.0167% | 5,986 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,438 |
| European (non-Finnish) | 0.000254% | 393,224 |

*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}

**BARD1** population constraint: LOEUF 1.087, pLI 1.1813e-19, missense-Z -0.16636; 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):

- **familial ovarian cancer** — Disputed (AD)
- **BARD1-related cancer predisposition** — Definitive (AD)

## Protein context {#protein}

Residue **94** lies in the 'interaction with brca1' region.

AlphaFold model confidence (whole protein): pLDDT 64.82, 28% of residues very-high.

**11 experimental structure(s)** (PDB): [1JM7](https://www.rcsb.org/structure/1JM7), [2NTE](https://www.rcsb.org/structure/2NTE), [2R1Z](https://www.rcsb.org/structure/2R1Z), [3C5R](https://www.rcsb.org/structure/3C5R), [3FA2](https://www.rcsb.org/structure/3FA2), [6M14](https://www.rcsb.org/structure/6M14) — incl. mutant structure 6M14.

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

*Describes the biological roles of BARD1 (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:** BARD1's established molecular role includes RNA binding. p.Asp94Ala falls in the interaction with brca1 region. In Reactome, BARD1 is annotated in disease pathway(s) including **Defective DNA double strand break response due to BARD1 loss of function**, **Defective DNA double strand break response due to BRCA1 loss of function**.

**Disease mechanism (Reactome):** BARD1 loss or alteration is curated in [Defective DNA double strand break response due to BARD1 loss of function](https://reactome.org/content/detail/R-HSA-9699150), [Defective DNA double strand break response due to BRCA1 loss of function](https://reactome.org/content/detail/R-HSA-9663199), [Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function](https://reactome.org/content/detail/R-HSA-9704331).

### Pathways affected {#pathways}

BARD1 participates in **21 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective DNA double strand break response due to BARD1 loss of function](https://reactome.org/content/detail/R-HSA-9699150) | other |
| ⚕ [Defective DNA double strand break response due to BRCA1 loss of function](https://reactome.org/content/detail/R-HSA-9663199) | other |
| ⚕ [Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function](https://reactome.org/content/detail/R-HSA-9704331) | other |
| ⚕ [Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function](https://reactome.org/content/detail/R-HSA-9704646) | other |
| ⚕ [Defective homologous recombination repair (HRR) due to BRCA1 loss of function](https://reactome.org/content/detail/R-HSA-9701192) | other |
| ⚕ [Impaired BRCA2 binding to PALB2](https://reactome.org/content/detail/R-HSA-9709603) | other |
| ⚕ [Impaired BRCA2 binding to RAD51](https://reactome.org/content/detail/R-HSA-9709570) | other |
| [Negative Regulation of DNA Double Strand Break Response](https://reactome.org/content/detail/R-HSA-9974237) | curated |
| [G2/M DNA damage checkpoint](https://reactome.org/content/detail/R-HSA-69473) | other |
| [HDR through Homologous Recombination (HRR)](https://reactome.org/content/detail/R-HSA-5685942) | other |
| [HDR through Single Strand Annealing (SSA)](https://reactome.org/content/detail/R-HSA-5685938) | other |
| [Homologous DNA Pairing and Strand Exchange](https://reactome.org/content/detail/R-HSA-5693579) | other |
| [Metalloprotease DUBs](https://reactome.org/content/detail/R-HSA-5689901) | other |
| [Nonhomologous End-Joining (NHEJ)](https://reactome.org/content/detail/R-HSA-5693571) | other |
| [Presynaptic phase of homologous DNA pairing and strand exchange](https://reactome.org/content/detail/R-HSA-5693616) | other |
| [Processing of DNA double-strand break ends](https://reactome.org/content/detail/R-HSA-5693607) | other |
| [Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks](https://reactome.org/content/detail/R-HSA-5693565) | other |
| [Regulation of TP53 Activity through Phosphorylation](https://reactome.org/content/detail/R-HSA-6804756) | other |
| [Resolution of D-loop Structures through Holliday Junction Intermediates](https://reactome.org/content/detail/R-HSA-5693568) | other |
| [Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)](https://reactome.org/content/detail/R-HSA-5693554) | other |
| [UCH proteinases](https://reactome.org/content/detail/R-HSA-5689603) | other |

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

**Molecular function:** RNA binding, protein homodimerization activity, protein heterodimerization activity.

**Biological process:** regulation of phosphorylation, positive regulation of apoptotic process, negative regulation of apoptotic process, negative regulation of protein export from nucleus, cellular response to ionizing radiation, protein K6-linked ubiquitination.

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-31.

**Submitter consensus:** unanimous (6/6 Uncertain significance).

**Submission history:** 6 submissions (2019–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Baylor Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-01-19 |
| Sema4, Sema4 | Uncertain significance | criteria provided, single submitter | curation | 2021-10-19 |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2019-07-29 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-09-12 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2026-01-31 |
| Color Diagnostics, LLC DBA Color Health | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-01-06 |

## Associated conditions {#conditions}

[hereditary breast carcinoma](https://sugi.bio/atlas/disease/hereditary-breast-carcinoma/), [hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/).

**Reported phenotype names (ClinVar):** Familial cancer of breast, Hereditary cancer-predisposing syndrome, not provided, none provided, BREAST CANCER, FAMILIAL, hereditary breast carcinoma, Hereditary breast cancer, Neoplastic Syndromes, Hereditary, Tumor predisposition, Hereditary Cancer Syndrome.

## Same-residue context {#hotspot}

Residue **94** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [BARD1 p.Asp94_Leu95insTer](/variant/bard1-p-asp94-leu95inster). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related BARD1 variant pages (same residue, condition, or type): [BARD1 p.Asp94Asn](/variant/bard1-p-asp94asn), [BARD1 p.Asp94Glu](/variant/bard1-p-asp94glu), [BARD1 p.Asp94=](/variant/bard1-p-asp94), [BARD1 p.Asp94_Leu95insTer](/variant/bard1-p-asp94-leu95inster), [BARD1 c.1314+1G>A](/variant/bard1-c-1314-plus-1g-a), [BARD1 c.1314+1G>T](/variant/bard1-c-1314-plus-1g-t), [BARD1 c.1396-1G>A](/variant/bard1-c-1396-minus-1g-a), [BARD1 c.1396-1G>C](/variant/bard1-c-1396-minus-1g-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 230637). 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.*