# NM_182643.3(DLC1):c.2858A>T (p.Asp953Val)

https://sugi.bio/variant/dlc1-p-asp953val

## Summary

**DLC1 p.Asp953Val (c.2858A>T)** is classified **Uncertain significance** in DLC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-08). AlphaMissense: likely pathogenic (0.607); Very rare (popmax 0.00263%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1435069232 · 1 submitter · AlphaMissense likely pathogenic · very rare (popmax 0.00263%, nfe)

## For patients & families {#patients}

This is a change in the DLC1 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 | [DLC1](https://sugi.bio/atlas/gene/DLC1/) |
| Protein change (HGVS p.) | p.Asp953Val |
| Coding change (HGVS c.) | c.2858A>T |
| MANE Select transcript | [NM_003746](https://www.ncbi.nlm.nih.gov/nuccore/NM_003746) (variant reported on NM_182643) |
| dbSNP | [rs1435069232](https://www.ncbi.nlm.nih.gov/snp/rs1435069232/) |
| Variant type | single nucleotide variant |
| Location | chr8:13099479-13099479 (GRCh38) |
| ClinVar | [VCV2529420](https://www.ncbi.nlm.nih.gov/clinvar/variation/2529420/) |

**All HGVS expressions:** `NC_000008.10:g.12956988T>A`, `NC_000008.11:g.13099479T>A`, `NG_015998.2:g.510127A>T`, `NM_001164271.2:c.1325A>T`, `NM_001316668.2:c.1649A>T`, `NM_001348081.2:c.2858A>T`, `NM_001348082.2:c.1325A>T`, `NM_001348083.1:c.1325A>T`, `NM_001348084.2:c.1325A>T`, `NM_001413124.1:c.2858A>T`, `NM_001413126.1:c.1325A>T`, `NM_001413127.1:c.1325A>T`, `NM_001413128.1:c.1325A>T`, `NM_001413129.1:c.1649A>T`, `NM_001413130.1:c.1640A>T`, `NM_001413131.1:c.1298A>T`, `NM_001413132.1:c.1784A>T`, `NM_001413133.1:c.1325A>T`, `NM_001413135.1:c.1547A>T`, `NM_001413136.1:c.1547A>T`, `NM_001413137.1:c.1298A>T`, `NM_001413138.1:c.1325A>T`, `NM_001413139.1:c.1547A>T`, `NM_001413140.1:c.1682A>T`, `NM_006094.5:c.1547A>T`, `NM_182643.3:c.2858A>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.607)
- REVEL 0.178 (moderately benign-leaning) — differs from AlphaMissense
- SaProt LLR -6.845 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense calls this damaging; REVEL and SaProt do not
- Conservation: phyloP 5.115, GERP 1.89, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 23.7**. 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.*
- 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 **0.00263%** (nfe) · FAF95 0.00188% · FAF99 0.00164% · 31/1,180,000 in the highest group · 31/1,461,884 alleles overall — very rare (popmax 0.00263%, 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.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 95.45, 94% of residues very-high.

**22 experimental structure(s)** (PDB): [11XU](https://www.rcsb.org/structure/11XU), [1CMI](https://www.rcsb.org/structure/1CMI), [3ZKE](https://www.rcsb.org/structure/3ZKE), [3ZKF](https://www.rcsb.org/structure/3ZKF), [6GZJ](https://www.rcsb.org/structure/6GZJ), [6GZL](https://www.rcsb.org/structure/6GZL) — incl. mutant structure 9NZ7.

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

*Describes the biological roles of DLC1 (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:** DLC1's established molecular role includes enzyme inhibitor activity. In Reactome, DLC1 is annotated in disease pathway(s) including **HCMV Early Events**.

**Disease mechanism (Reactome):** DLC1 loss or alteration is curated in [HCMV Early Events](https://reactome.org/content/detail/R-HSA-9609690).

### Pathways affected {#pathways}

DLC1 participates in **24 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [HCMV Early Events](https://reactome.org/content/detail/R-HSA-9609690) | curated |
| [AURKA Activation by TPX2](https://reactome.org/content/detail/R-HSA-8854518) | curated |
| [Activation of BIM and translocation to mitochondria ](https://reactome.org/content/detail/R-HSA-111446) | curated |
| [Amplification  of signal from unattached  kinetochores via a MAD2  inhibitory signal](https://reactome.org/content/detail/R-HSA-141444) | curated |
| [Anchoring of the basal body to the plasma membrane](https://reactome.org/content/detail/R-HSA-5620912) | curated |
| [COPI-independent Golgi-to-ER retrograde traffic](https://reactome.org/content/detail/R-HSA-6811436) | curated |
| [COPI-mediated anterograde transport](https://reactome.org/content/detail/R-HSA-6807878) | curated |
| [EML4 and NUDC in mitotic spindle formation](https://reactome.org/content/detail/R-HSA-9648025) | curated |
| [HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand](https://reactome.org/content/detail/R-HSA-3371497) | curated |
| [Intraflagellar transport](https://reactome.org/content/detail/R-HSA-5620924) | curated |
| [Loss of Nlp from mitotic centrosomes](https://reactome.org/content/detail/R-HSA-380259) | curated |
| [Loss of proteins required for interphase microtubule organization from the centrosome](https://reactome.org/content/detail/R-HSA-380284) | curated |
| [MHC class II antigen presentation](https://reactome.org/content/detail/R-HSA-2132295) | curated |
| [Macroautophagy](https://reactome.org/content/detail/R-HSA-1632852) | curated |
| [Mitotic Prometaphase](https://reactome.org/content/detail/R-HSA-68877) | curated |
| [Neutrophil degranulation](https://reactome.org/content/detail/R-HSA-6798695) | curated |
| [Processing of antigen in germinal center B cells](https://reactome.org/content/detail/R-HSA-9979719) | curated |
| [RHO GTPases Activate Formins](https://reactome.org/content/detail/R-HSA-5663220) | curated |
| [Recruitment of NuMA to mitotic centrosomes](https://reactome.org/content/detail/R-HSA-380320) | curated |
| [Recruitment of mitotic centrosome proteins and complexes](https://reactome.org/content/detail/R-HSA-380270) | curated |
| [Regulation of PLK1 Activity at G2/M Transition](https://reactome.org/content/detail/R-HSA-2565942) | curated |
| [Resolution of Sister Chromatid Cohesion](https://reactome.org/content/detail/R-HSA-2500257) | curated |
| [Separation of Sister Chromatids](https://reactome.org/content/detail/R-HSA-2467813) | curated |
| [Aggrephagy](https://reactome.org/content/detail/R-HSA-9646399) | electronic |

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

**Molecular function:** enzyme inhibitor activity.

**Biological process:** substantia nigra development, negative regulation of phosphorylation, negative regulation of DNA strand resection involved in replication fork processing.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-08-08.

**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 | 2025-08-08 |

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

## Similar variants {#similar}

Related DLC1 variant pages (same residue, condition, or type): [DLC1 c.2991-5C>A](/variant/dlc1-c-2991-minus-5c-a), [DLC1 p.Ala1268Val](/variant/dlc1-p-ala1268val), [DLC1 p.Ala1278Thr](/variant/dlc1-p-ala1278thr), [DLC1 p.Ala167Pro](/variant/dlc1-p-ala167pro), [DLC1 p.Ala350Val](/variant/dlc1-p-ala350val), [DLC1 p.Ala752Gly](/variant/dlc1-p-ala752gly), [DLC1 p.Ala821Thr](/variant/dlc1-p-ala821thr), [DLC1 p.Ala821Val](/variant/dlc1-p-ala821val).

### 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 2529420). 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.*