# NM_004632.4(DAP3):c.257G>T (p.Arg86Leu)

https://sugi.bio/variant/dap3-p-arg86leu

## Summary

**DAP3 p.Arg86Leu (c.257G>T)** is classified **Uncertain significance** in DAP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-01). AlphaMissense: likely benign (0.3249); Very rare (popmax 0.000424%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.000424%, nfe)

## For patients & families {#patients}

This is a change in the DAP3 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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 | [DAP3](https://sugi.bio/atlas/gene/DAP3/) |
| Protein change (HGVS p.) | p.Arg86Leu |
| Coding change (HGVS c.) | c.257G>T |
| MANE Select transcript | [NM_004632](https://www.ncbi.nlm.nih.gov/nuccore/NM_004632) |
| Variant type | single nucleotide variant |
| Location | chr1:155721605-155721605 (GRCh38) |
| ClinVar | [VCV3270859](https://www.ncbi.nlm.nih.gov/clinvar/variation/3270859/) |

**All HGVS expressions:** `NC_000001.10:g.155691396G>T`, `NC_000001.11:g.155721605G>T`, `NM_001199849.1:c.257G>T`, `NM_001199850.1:c.169-3777G>T`, `NM_001199851.1:c.134G>T`, `NM_004632.4:c.257G>T`, `NM_033657.2:c.257G>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.3249)
- REVEL 0.288 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -7.012 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **donor loss** (Δ 0.29) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 6.598, GERP 0.908, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 26.9**. 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 0.95** across the covering region of the MANE Select transcript (155,709,780–155,738,239), spanning 28,459 bp. Chi-square p 0.25. 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 **0.29**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.29**, acceptor gain **0.00**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.000424%** (nfe) · FAF95 0.000124% · FAF99 9e-05% · 5/1,179,980 in the highest group · 5/1,461,838 alleles overall — very rare (popmax 0.000424%, nfe).

*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}

**DAP3** population constraint: LOEUF 0.706, pLI 0.00081756, missense-Z 0.75609. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **86** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 85.23, 69% of residues very-high.

**86 experimental structure(s)** (PDB): [3J9M](https://www.rcsb.org/structure/3J9M), [6NU2](https://www.rcsb.org/structure/6NU2), [6NU3](https://www.rcsb.org/structure/6NU3), [6RW4](https://www.rcsb.org/structure/6RW4), [6RW5](https://www.rcsb.org/structure/6RW5), [6VLZ](https://www.rcsb.org/structure/6VLZ).

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

*Describes the biological roles of DAP3 (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:** DAP3's established molecular role includes RNA binding.


### Pathways affected {#pathways}

DAP3 participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Mitochondrial ribosome-associated quality control](https://reactome.org/content/detail/R-HSA-9937383) | curated |
| [Mitochondrial translation termination](https://reactome.org/content/detail/R-HSA-5419276) | curated |
| [Mitochondrial translation elongation](https://reactome.org/content/detail/R-HSA-5389840) | electronic |
| [Mitochondrial translation initiation](https://reactome.org/content/detail/R-HSA-5368286) | electronic |

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

**Molecular function:** RNA binding, structural constituent of ribosome, GTPase activity.

**Biological process:** mitochondrial translation.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-05-01.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-05-01 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related DAP3 variant pages (same residue, condition, or type): [YY1AP1 c.-151-185G>A](/variant/yy1ap1-c-minus-151-minus-185g-a), [DAP3 p.Arg20Cys](/variant/dap3-p-arg20cys), [DAP3 p.Val240Phe](/variant/dap3-p-val240phe), [YY1AP1 c.-151-68T>C](/variant/yy1ap1-c-minus-151-minus-68t-c), [YY1AP1 c.-30C>T](/variant/yy1ap1-c-minus-30c-t), [YY1AP1 c.-49T>C](/variant/yy1ap1-c-minus-49t-c), [YY1AP1 c.-60T>C](/variant/yy1ap1-c-minus-60t-c), [YY1AP1 c.-95G>A](/variant/yy1ap1-c-minus-95g-a).

### 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 3270859). 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.*