# NM_000795.4(DRD2):c.1211C>T (p.Pro404Leu)

https://sugi.bio/variant/drd2-p-pro404leu

## Summary

**DRD2 p.Pro404Leu (c.1211C>T)** is classified **Uncertain significance** in DRD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-25). AlphaMissense: likely pathogenic (0.6711); Very rare (popmax 0.0011%, sas).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely pathogenic · very rare (popmax 0.0011%, sas)

## For patients & families {#patients}

This is a change in the DRD2 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 | [DRD2](https://sugi.bio/atlas/gene/DRD2/) |
| Protein change (HGVS p.) | p.Pro404Leu |
| Coding change (HGVS c.) | c.1211C>T |
| MANE Select transcript | [NM_000795](https://www.ncbi.nlm.nih.gov/nuccore/NM_000795) |
| Variant type | single nucleotide variant |
| Location | chr11:113410848-113410848 (GRCh38) |
| ClinVar | [VCV4662128](https://www.ncbi.nlm.nih.gov/clinvar/variation/4662128/) |

**All HGVS expressions:** `NC_000011.10:g.113410848G>A`, `NC_000011.9:g.113281570G>A`, `NG_008841.1:g.69432C>T`, `NM_000795.4:c.1211C>T`, `NM_001440368.1:c.1208C>T`, `NM_016574.4:c.1124C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.6711)
- REVEL 0.429 (indeterminate)
- SaProt LLR -8.482 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense calls this damaging; SaProt does not; REVEL makes no call
- Conservation: phyloP 9.918, GERP 2.46, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 33.0**. 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 0.49** across the covering region of the MANE Select transcript (113,410,730–113,412,669), spanning 1,939 bp. Chi-square p 3.2e-09. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.34 acceptor loss), 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 **0.0011%** (sas) · 1/91,084 in the highest group · 1/1,461,860 alleles overall — very rare (popmax 0.0011%, sas).

*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}


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.


### 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-11-25.

**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 | 2025-11-25 |

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

## Similar variants {#similar}

Related DRD2 variant pages (same residue, condition, or type): [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), [DRD2 p.Pro300His](/variant/drd2-p-pro300his), [DRD2 p.Val223Ile](/variant/drd2-p-val223ile).

### 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 4662128). 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.*