# NM_000797.4(DRD4):c.1056C>G (p.Val352=)

https://sugi.bio/variant/drd4-p-val352

## Summary

**DRD4 p.Val352= (c.1056C>G)** is classified **Benign** in DRD4 (ClinVar, No assertion criteria, 2 submitters; last evaluated 2019-03-21). Common (popmax 5.41%, afr) — too common for a highly-penetrant pathogenic allele; Associated with DRD4-related disorder.

**At a glance:** Benign · review: No assertion criteria · rsID rs201878429 · 2 submitters · 1 linked condition · common (popmax 5.41%, afr) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the DRD4 gene that is classified as benign — not considered disease-causing, submitted by 2 submitters, and is linked to DRD4-related disorder.

*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 | [DRD4](https://sugi.bio/atlas/gene/DRD4/) |
| Protein change (HGVS p.) | p.Val352= |
| Coding change (HGVS c.) | c.1056C>G |
| MANE Select transcript | [NM_000797](https://www.ncbi.nlm.nih.gov/nuccore/NM_000797) |
| dbSNP | [rs201878429](https://www.ncbi.nlm.nih.gov/snp/rs201878429/) |
| Variant type | single nucleotide variant |
| Location | chr11:640305-640305 (GRCh38) |
| ClinVar | [VCV3056794](https://www.ncbi.nlm.nih.gov/clinvar/variation/3056794/) |

**All HGVS expressions:** `NC_000011.10:g.640305C>G`, `NC_000011.9:g.640305C>G`, `NG_021241.1:g.8001C>G`, `NG_121482.1:g.213C>G`, `NM_000797.4:c.1056C>G`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 5.41%, afr) — too common for a highly-penetrant pathogenic allele.

- **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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor gain** (Δ 0.36) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -0.027, GERP -2.15, phastCons 0.809 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 15.74**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.09**, acceptor gain **0.00**, donor gain **0.36**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.09**, acceptor gain **0.00**, donor gain **0.36**.
- Pangolin: Δ**0.26** (gain), gain 0.26 / loss 0.25. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **5.41%** (afr) · FAF95 5.27% · FAF99 5.21% · 3,965/73,256 in the highest group · 4,690/1,504,480 alleles overall — common (popmax 5.41%, afr) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 5.41% | 18 |
| Admixed American | 0.445% | 225 |
| Remaining individuals (not grpmax-eligible) | 0.43% | 232 |
| Middle Eastern | 0.115% | 867 |
| European (non-Finnish) | 0.0204% | 4,904 |
| South Asian | 0.0144% | 6,960 |

*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}

**DRD4** population constraint: LOEUF 1.952, pLI 7.1662e-14, missense-Z -6.3234. *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 **352** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 78.06, 47% of residues very-high.

**2 experimental structure(s)** (PDB): [5WIU](https://www.rcsb.org/structure/5WIU), [5WIV](https://www.rcsb.org/structure/5WIV).

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

*Describes the biological roles of DRD4 (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:** DRD4's established molecular role includes dopamine neurotransmitter receptor activity, coupled via Gi/Go.


### Pathways affected {#pathways}

DRD4 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Dopamine receptors](https://reactome.org/content/detail/R-HSA-390651) | curated |
| [G alpha (i) signalling events](https://reactome.org/content/detail/R-HSA-418594) | curated |

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

**Molecular function:** dopamine neurotransmitter receptor activity, coupled via Gi/Go, dopamine neurotransmitter receptor activity, SH3 domain binding, dopamine binding, identical protein binding, epinephrine binding.

**Biological process:** intracellular calcium ion homeostasis, adenylate cyclase-inhibiting dopamine receptor signaling pathway, response to histamine, positive regulation of MAPK cascade, arachidonate secretion, negative regulation of protein secretion.

## Clinical significance {#significance}

**Benign** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2019-03-21.

**Submitter consensus:** unanimous (1/1 Benign).

**Submission history:** 5 submissions (2019); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Benign | no assertion criteria provided | clinical testing | 2019-03-21 |
| Dr. Peter K. Rogan Lab, Western University |  | no classification provided | in vitro |  |

## Associated conditions {#conditions}

[DRD4-related disorder](https://sugi.bio/atlas/disease/drd4-related-disorder/).

**Reported phenotype names (ClinVar):** DRD4-related disorder, Thymoma, Colon adenocarcinoma, Sarcoma, Ovarian serous cystadenocarcinoma, DRD4-related condition.

## Similar variants {#similar}

Related DRD4 variant pages (same residue, condition, or type): [DRD4 p.Ala36Val](/variant/drd4-p-ala36val), [DRD4 p.Cys372Tyr](/variant/drd4-p-cys372tyr), [DRD4 p.Pro246His](/variant/drd4-p-pro246his), [DRD4 c.285+7C>T](/variant/drd4-c-285-plus-7c-t), [DRD4 p.Ala228=](/variant/drd4-p-ala228), [DRD4 p.Ala78Thr](/variant/drd4-p-ala78thr), [DRD4 p.Ala84Thr](/variant/drd4-p-ala84thr), [DRD4 p.Arg412Leu](/variant/drd4-p-arg412leu).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2026-10-14); 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 3056794). 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.*