# NM_000798.5(DRD5):c.978C>T (p.Pro326=)

https://sugi.bio/variant/drd5-p-pro326

## Summary

**DRD5 p.Pro326= (c.978C>T)** is classified **Conflicting classifications of pathogenicity** in DRD5 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-11-26). Common (popmax 70.9%, mid) — too common for a highly-penetrant pathogenic allele; Associated with hereditary attention deficit-hyperactivity disorder.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs6283 · 2 submitters · 2 linked conditions · common (popmax 70.9%, mid) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the DRD5 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 2 submitters, and is linked to hereditary attention deficit-hyperactivity 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 | [DRD5](https://sugi.bio/atlas/gene/DRD5/) |
| Protein change (HGVS p.) | p.Pro326= |
| Coding change (HGVS c.) | c.978C>T |
| MANE Select transcript | [NM_000798](https://www.ncbi.nlm.nih.gov/nuccore/NM_000798) |
| dbSNP | [rs6283](https://www.ncbi.nlm.nih.gov/snp/rs6283/) |
| Variant type | single nucleotide variant |
| Location | chr4:9783007-9783007 (GRCh38) |
| ClinVar | [VCV2507407](https://www.ncbi.nlm.nih.gov/clinvar/variation/2507407/) |

**All HGVS expressions:** `NC_000004.11:g.9784631C>T`, `NC_000004.12:g.9783007C>T`, `NG_011540.2:g.262263G>A`, `NG_012024.1:g.6374C>T`, `NM_000798.5:c.978C>T`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 70.9%, mid) — 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 (below), not from a missing predictor score.
- Conservation: phyloP -4.082, GERP -3.3 — fast-evolving / accelerated position
- CADD: **PHRED 1.804**. 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: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **70.9%** (mid) · FAF95 69.1% · FAF99 68.4% · 4,297/6,062 in the highest group · 1,051,677/1,613,976 alleles overall — common (popmax 70.9%, mid) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Amish (not grpmax-eligible) | 74.1% | 1 |
| Ashkenazi Jewish (not grpmax-eligible) | 74% | 1 |
| Middle Eastern (grpmax) | 70.9% | 1 |
| European (non-Finnish) | 65.9% | 2 |
| Remaining individuals (not grpmax-eligible) | 65.5% | 2 |
| Admixed American | 65.4% | 2 |
| East Asian | 61.3% | 2 |
| South Asian | 60.7% | 2 |
| African / African-American | 60.6% | 2 |
| Finnish (not grpmax-eligible) | 59.9% | 2 |

Amish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**DRD5** population constraint: LOEUF 1.851, pLI 0.094369, missense-Z -1.3312; ClinGen dosage — haploinsufficiency 0/3, triplosensitivity 0/3. *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 69.45, 31% of residues very-high.

**1 experimental structure(s)** (PDB): [8IRV](https://www.rcsb.org/structure/8IRV).

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

*Describes the biological roles of DRD5 (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:** DRD5's established molecular role includes dopamine neurotransmitter receptor activity.


### Pathways affected {#pathways}

DRD5 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Dopamine receptors](https://reactome.org/content/detail/R-HSA-390651) | curated |
| [G alpha (s) signalling events](https://reactome.org/content/detail/R-HSA-418555) | curated |

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

**Molecular function:** dopamine neurotransmitter receptor activity, dopamine binding.

**Biological process:** adenylate cyclase-activating G protein-coupled receptor signaling pathway, adenylate cyclase-activating dopamine receptor signaling pathway, regulation of blood pressure, cellular response to catecholamine stimulus, reactive oxygen species metabolic process.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2024-11-26.

**Submitter consensus:** conflicting (1 Uncertain significance, 1 Benign).

**Submission history:** 2 submissions (2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic | Uncertain significance | criteria provided, single submitter | clinical testing |  |
| Blueprint Genetics | Benign | criteria provided, single submitter | clinical testing | 2024-11-26 |

## Associated conditions {#conditions}

[hereditary attention deficit-hyperactivity disorder](https://sugi.bio/atlas/disease/hereditary-attention-deficit-hyperactivity-disorder/), [schizophrenia](https://sugi.bio/atlas/disease/schizophrenia/).

**Reported phenotype names (ClinVar):** Hereditary attention deficit-hyperactivity disorder, Schizophrenia, not specified, AllHighlyPenetrant, HYPERACTIVITY OF CHILDHOOD.

## Similar variants {#similar}

Related DRD5 variant pages (same residue, condition, or type): [DRD5 c.*47T>C](/variant/drd5-c-star-47t-c), [DRD5 p.Val59Met](/variant/drd5-p-val59met), [DRD5 c.-226G>C](/variant/drd5-c-minus-226g-c), [DRD5 c.*178G>T](/variant/drd5-c-star-178g-t), [DRD5 p.Leu88Phe](/variant/drd5-p-leu88phe), [DRD5 p.Ala10Val](/variant/drd5-p-ala10val), [DRD5 p.Ala111Glu](/variant/drd5-p-ala111glu), [DRD5 p.Ala164Glu](/variant/drd5-p-ala164glu).

### 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 2507407). 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.*