# NM_001330311.2(DVL1):c.1035C>T (p.Ser345=)

https://sugi.bio/variant/dvl1-p-ser345

## Summary

**DVL1 p.Ser345= (c.1035C>T)** is classified **Likely benign** in DVL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-15). Ultra-rare (popmax 0.0107%, afr).

**At a glance:** Likely benign · review: Single submitter · rsID rs750694359 · 1 submitter · ultra-rare (popmax 0.0107%, afr)

## For patients & families {#patients}

This is a change in the DVL1 gene that is classified as likely benign — not considered disease-causing, 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 | [DVL1](https://sugi.bio/atlas/gene/DVL1/) |
| Protein change (HGVS p.) | p.Ser345= |
| Coding change (HGVS c.) | c.1035C>T |
| MANE Select transcript | [NM_001330311](https://www.ncbi.nlm.nih.gov/nuccore/NM_001330311) |
| dbSNP | [rs750694359](https://www.ncbi.nlm.nih.gov/snp/rs750694359/) |
| Variant type | single nucleotide variant |
| Location | chr1:1339601-1339601 (GRCh38) |
| ClinVar | [VCV1639467](https://www.ncbi.nlm.nih.gov/clinvar/variation/1639467/) |

**All HGVS expressions:** `NC_000001.10:g.1274981G>A`, `NC_000001.11:g.1339601G>A`, `NG_008048.2:g.14512C>T`, `NM_001330311.2:c.1035C>T`, `NM_004421.3:c.1035C>T`

## Computational & population evidence {#evidence}

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

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 1.602, GERP -4.78, phastCons 1 — weakly conserved position
- CADD: **PHRED 6.979**. 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: **below the reporting threshold**. This position is scored for a different substitution (G>C, Δ0.77 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0107%** (afr) · FAF95 0.00529% · FAF99 0.00381% · 8/74,804 in the highest group · 10/1,607,236 alleles overall — ultra-rare (popmax 0.0107%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.0107% | 9,351 |
| Admixed American | 0.00167% | 59,758 |
| Remaining individuals (not grpmax-eligible) | 0.00161% | 62,158 |

*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}

**DVL1** population constraint: LOEUF 1.046, pLI 1.2538e-14, missense-Z -2.5647. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 60.70, 19% of residues very-high.

**3 experimental structure(s)** (PDB): [6LCA](https://www.rcsb.org/structure/6LCA), [6LCB](https://www.rcsb.org/structure/6LCB), [6TTK](https://www.rcsb.org/structure/6TTK).

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

*Describes the biological roles of DVL1 (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:** DVL1's established molecular role includes frizzled binding. In Reactome, DVL1 is annotated in disease pathway(s) including **WNT5:FZD7-mediated leishmania damping**.

**Disease mechanism (Reactome):** DVL1 loss or alteration is curated in [WNT5:FZD7-mediated leishmania damping](https://reactome.org/content/detail/R-HSA-9673324).

### Pathways affected {#pathways}

DVL1 participates in **8 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [WNT5:FZD7-mediated leishmania damping](https://reactome.org/content/detail/R-HSA-9673324) | electronic |
| [Degradation of DVL](https://reactome.org/content/detail/R-HSA-4641258) | curated |
| [RHO GTPases Activate Formins](https://reactome.org/content/detail/R-HSA-5663220) | curated |
| [WNT mediated activation of DVL](https://reactome.org/content/detail/R-HSA-201688) | curated |
| [Disassembly of the destruction complex and recruitment of AXIN to the membrane](https://reactome.org/content/detail/R-HSA-4641262) | electronic |
| [Negative regulation of TCF-dependent signaling by DVL-interacting proteins](https://reactome.org/content/detail/R-HSA-5368598) | electronic |
| [PCP/CE pathway](https://reactome.org/content/detail/R-HSA-4086400) | electronic |
| [TCF dependent signaling in response to WNT](https://reactome.org/content/detail/R-HSA-201681) | electronic |

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

**Molecular function:** frizzled binding, enzyme binding, protein kinase binding, identical protein binding.

**Biological process:** regulation of DNA-templated transcription, neural tube development, positive regulation of proteasomal ubiquitin-dependent protein catabolic process, regulation of protein localization, protein localization to nucleus, positive regulation of transcription by RNA polymerase II.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-12-15.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-12-15 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related DVL1 variant pages (same residue, condition, or type): [DVL1 p.Ser345Asn](/variant/dvl1-p-ser345asn), [DVL1 p.Ala125Val](/variant/dvl1-p-ala125val), [DVL1 p.Ala288Val](/variant/dvl1-p-ala288val), [DVL1 p.Ala361Thr](/variant/dvl1-p-ala361thr), [DVL1 p.Ala368Val](/variant/dvl1-p-ala368val), [DVL1 p.Ala667Pro](/variant/dvl1-p-ala667pro), [DVL1 p.Arg108Trp](/variant/dvl1-p-arg108trp), [DVL1 p.Arg116Gln](/variant/dvl1-p-arg116gln).

### 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 1639467). 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.*