# NM_004423.4(DVL3):c.1482C>T (p.Phe494=)

https://sugi.bio/variant/dvl3-p-phe494

## Summary

**DVL3 p.Phe494= (c.1482C>T)** is classified **Likely benign** in DVL3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-12). Ultra-rare (popmax 0.0143%, sas).

**At a glance:** Likely benign · review: Single submitter · rsID rs757423280 · 1 submitter · ultra-rare (popmax 0.0143%, sas)

## For patients & families {#patients}

This is a change in the DVL3 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 | [DVL3](https://sugi.bio/atlas/gene/DVL3/) |
| Protein change (HGVS p.) | p.Phe494= |
| Coding change (HGVS c.) | c.1482C>T |
| MANE Select transcript | [NM_004423](https://www.ncbi.nlm.nih.gov/nuccore/NM_004423) |
| dbSNP | [rs757423280](https://www.ncbi.nlm.nih.gov/snp/rs757423280/) |
| Variant type | single nucleotide variant |
| Location | chr3:184168049-184168049 (GRCh38) |
| ClinVar | [VCV1907258](https://www.ncbi.nlm.nih.gov/clinvar/variation/1907258/) |

**All HGVS expressions:** `LRG_1269:g.17739C>T`, `LRG_1269t1:c.1482C>T`, `NC_000003.11:g.183885837C>T`, `NC_000003.12:g.184168049C>T`, `NG_046860.1:g.17739C>T`, `NM_004423.4:c.1482C>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 -3.525, GERP -2.77 — fast-evolving / accelerated position
- CADD: **PHRED 12.23**. 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 (C>A, Δ0.83 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 **0.0143%** (sas) · FAF95 0.00844% · FAF99 0.00661% · 13/91,088 in the highest group · 55/1,614,090 alleles overall — ultra-rare (popmax 0.0143%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.0143% | 7,007 |
| Remaining individuals (not grpmax-eligible) | 0.0064% | 15,622 |
| African / African-American | 0.00534% | 18,738 |
| European (non-Finnish) | 0.00288% | 34,706 |

*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}

**DVL3** population constraint: LOEUF 0.536, pLI 0.69837, missense-Z 2.4758. *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 **494** lies in the dep domain.

AlphaFold model confidence (whole protein): pLDDT 59.50, 20% of residues very-high.

**9 experimental structure(s)** (PDB): [6V7O](https://www.rcsb.org/structure/6V7O), [6ZBQ](https://www.rcsb.org/structure/6ZBQ), [6ZBZ](https://www.rcsb.org/structure/6ZBZ), [6ZC3](https://www.rcsb.org/structure/6ZC3), [6ZC4](https://www.rcsb.org/structure/6ZC4), [6ZC6](https://www.rcsb.org/structure/6ZC6).

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

*Describes the biological roles of DVL3 (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:** DVL3's established molecular role includes protease binding. p.Phe494= falls in the dep domain. In Reactome, DVL3 is annotated in disease pathway(s) including **WNT5:FZD7-mediated leishmania damping**.

**Disease mechanism (Reactome):** DVL3 loss or alteration is curated in [WNT5:FZD7-mediated leishmania damping](https://reactome.org/content/detail/R-HSA-9673324).

### Pathways affected {#pathways}

DVL3 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:** protease binding, signaling receptor binding, frizzled binding, beta-catenin binding, small GTPase binding.

**Biological process:** small GTPase-mediated signal transduction, regulation of protein localization, non-canonical Wnt signaling pathway, positive regulation of DNA-templated transcription, positive regulation of transcription by RNA polymerase II, positive regulation of JNK cascade.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-03-12.

**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 | 2024-03-12 |

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

## Similar variants {#similar}

Related DVL3 variant pages (same residue, condition, or type): [DVL3 c.1715-1G>A](/variant/dvl3-c-1715-minus-1g-a), [DVL3 p.Ala359Thr](/variant/dvl3-p-ala359thr), [DVL3 p.Ala565Val](/variant/dvl3-p-ala565val), [DVL3 p.Ala593Val](/variant/dvl3-p-ala593val), [DVL3 p.Ala629Thr](/variant/dvl3-p-ala629thr), [DVL3 p.Arg145Gln](/variant/dvl3-p-arg145gln), [DVL3 p.Arg157Gln](/variant/dvl3-p-arg157gln), [DVL3 p.Arg166Trp](/variant/dvl3-p-arg166trp).

### 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 1907258). 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.*