# NM_000795.4(DRD2):c.928C>T (p.Pro310Ser)

https://sugi.bio/variant/drd2-p-pro310ser

## Summary

**DRD2 p.Pro310Ser (c.928C>T)** is classified **Conflicting classifications of pathogenicity** in DRD2 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-06-01). AlphaMissense: likely benign (0.0645); Low-frequency (popmax 2.76%, mid); Associated with DRD2-associated Dystonia.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs1800496 · 7 submitters · 2 linked conditions · AlphaMissense likely benign · low-frequency (popmax 2.76%, mid)

## For patients & families {#patients}

This is a change in the DRD2 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 7 submitters, and is linked to DRD2-associated Dystonia.

*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 | [DRD2](https://sugi.bio/atlas/gene/DRD2/) |
| Protein change (HGVS p.) | p.Pro310Ser |
| Coding change (HGVS c.) | c.928C>T |
| MANE Select transcript | [NM_000795](https://www.ncbi.nlm.nih.gov/nuccore/NM_000795) |
| dbSNP | [rs1800496](https://www.ncbi.nlm.nih.gov/snp/rs1800496/) |
| Variant type | single nucleotide variant |
| Location | chr11:113412766-113412766 (GRCh38) |
| ClinVar | [VCV256812](https://www.ncbi.nlm.nih.gov/clinvar/variation/256812/) |

**All HGVS expressions:** `NC_000011.10:g.113412766G>A`, `NC_000011.9:g.113283488G>A`, `NG_008841.1:g.67514C>T`, `NM_000795.4:c.928C>T`, `NM_016574.4:c.841C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0645)
- REVEL 0.053 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -5.645 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 4.908, GERP -2.43, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 14.97**. 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 0.93** across the covering region of the MANE Select transcript (113,412,670–113,415,503), spanning 2,833 bp. Chi-square p 0.35. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for DRD2 (489 scored positions, the nearest 1 base away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency (gnomAD v4.1): grpmax **2.76%** (mid) · FAF95 2.42% · FAF99 2.28% · 167/6,058 in the highest group · 1,751/1,613,788 alleles overall — low-frequency (popmax 2.76%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 2.76% | 36 |
| Ashkenazi Jewish (not grpmax-eligible) | 1.66% | 60 |
| Remaining individuals (not grpmax-eligible) | 0.246% | 406 |
| South Asian | 0.123% | 813 |
| Admixed American | 0.11% | 909 |
| European (non-Finnish) | 0.0616% | 1,623 |
| African / African-American | 0.04% | 2,501 |
| Finnish (not grpmax-eligible) | 0.00625% | 16,008 |

*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}

**DRD2** population constraint: LOEUF 0.372, pLI 0.99986, missense-Z 3.3779. *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 **310** lies in the 'interaction with ppp1r9b' region; the 'disordered' region; a UniProt-annotated variant site (in).

AlphaFold model confidence (whole protein): pLDDT 72.49, 37% of residues very-high.

**11 experimental structure(s)** (PDB): [5AER](https://www.rcsb.org/structure/5AER), [6CM4](https://www.rcsb.org/structure/6CM4), [6LUQ](https://www.rcsb.org/structure/6LUQ), [6VMS](https://www.rcsb.org/structure/6VMS), [7DFP](https://www.rcsb.org/structure/7DFP), [7JVR](https://www.rcsb.org/structure/7JVR) — incl. mutant structure 8TZQ.

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

*Describes the biological roles of DRD2 (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:** DRD2's established molecular role includes dopamine neurotransmitter receptor activity, coupled via Gi/Go. p.Pro310Ser falls in the interaction with ppp1r9b region.


### Pathways affected {#pathways}

DRD2 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Dopamine receptors](https://reactome.org/content/detail/R-HSA-390651) | curated |

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

**Molecular function:** dopamine neurotransmitter receptor activity, coupled via Gi/Go, G-protein alpha-subunit binding, heterotrimeric G-protein binding, identical protein binding.

**Biological process:** intracellular calcium ion homeostasis, adenylate cyclase-inhibiting dopamine receptor signaling pathway, phospholipase C-activating G protein-coupled receptor signaling pathway, positive regulation of cytokinesis, response to histamine, intracellular signal transduction.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-06-01.

**Submitter consensus:** conflicting (5 Likely benign, 2 Uncertain significance).

**Submission history:** 7 submissions (2016–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Eurofins Ntd Llc (ga) | Uncertain significance | criteria provided, single submitter | clinical testing | 2016-09-06 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-12 |
| PreventionGenetics, part of Exact Sciences | Likely benign | criteria provided, single submitter | clinical testing |  |
| New York Genome Center | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-07-09 |
| Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre | Likely benign | criteria provided, single submitter | clinical testing | 2025-07-30 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-11-24 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2026-06-01 |

## Associated conditions {#conditions}

[DRD2-associated Dystonia](https://sugi.bio/atlas/disease/drd2-associated-dystonia/), [dystonic disorder](https://sugi.bio/atlas/disease/dystonic-disorder/).

**Reported phenotype names (ClinVar):** DRD2-associated Dystonia, not specified, not provided, Dystonic disorder, Dystonia, AllHighlyPenetrant, none provided.

## Similar variants {#similar}

Related DRD2 variant pages (same residue, condition, or type): [DRD2 p.Pro310=](/variant/drd2-p-pro310), [DRD2 p.Pro310Leu](/variant/drd2-p-pro310leu), [DRD2 p.Arg274Gln](/variant/drd2-p-arg274gln), [DRD2 p.Gln366Lys](/variant/drd2-p-gln366lys), [DRD2 p.Glu99Lys](/variant/drd2-p-glu99lys), [DRD2 p.Gly261Arg](/variant/drd2-p-gly261arg), [DRD2 p.His316Pro](/variant/drd2-p-his316pro), [DRD2 p.Ile431Thr](/variant/drd2-p-ile431thr).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 256812). 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.*