# NM_000787.4(DBH):c.1221C>G (p.Phe407Leu)

https://sugi.bio/variant/dbh-p-phe407leu

## Summary

**DBH p.Phe407Leu (c.1221C>G)** is classified **Uncertain significance** in DBH (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-23). AlphaMissense: likely pathogenic (0.9828); Very rare (popmax 0.00167%, amr); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs367783759 · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 0.00167%, amr)

## For patients & families {#patients}

This is a change in the DBH gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to Inborn genetic diseases.

*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 | [DBH](https://sugi.bio/atlas/gene/DBH/) |
| Protein change (HGVS p.) | p.Phe407Leu |
| Coding change (HGVS c.) | c.1221C>G |
| MANE Select transcript | [NM_000787](https://www.ncbi.nlm.nih.gov/nuccore/NM_000787) |
| dbSNP | [rs367783759](https://www.ncbi.nlm.nih.gov/snp/rs367783759/) |
| Variant type | single nucleotide variant |
| Location | chr9:133651663-133651663 (GRCh38) |
| ClinVar | [VCV2386226](https://www.ncbi.nlm.nih.gov/clinvar/variation/2386226/) |

**All HGVS expressions:** `NC_000009.11:g.136516785C>G`, `NC_000009.12:g.133651663C>G`, `NG_008645.1:g.20301C>G`, `NM_000787.4:c.1221C>G`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.9828)
- REVEL 0.619 (indeterminate)
- SaProt LLR -12.403 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL makes no call
- Conservation: phyloP -9.524, GERP -2.79 — fast-evolving / accelerated position
- AlphaMissense ranks this among the **top 4%** most-pathogenic-predicted substitutions in DBH (of 3,651 modeled).
- CADD: **PHRED 12.72**. 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 1.00** across the covering region of the MANE Select transcript (133,636,372–133,658,444), spanning 22,072 bp. Chi-square p 0.96. 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 (C>T, Δ0.30 acceptor 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 **0.00167%** (amr) · FAF95 0.000803% · FAF99 0.00065% · 1/60,014 in the highest group · 18/1,613,730 alleles overall — very rare (popmax 0.00167%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00338% | 29,602 |
| Admixed American (grpmax) | 0.00167% | 60,014 |
| European (non-Finnish) | 0.00136% | 73,752 |

Ashkenazi Jewish 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}

**DBH** population constraint: LOEUF 0.936, pLI 9.4704e-13, missense-Z 0.35624; ClinGen dosage — haploinsufficiency 30, triplosensitivity 0 (0–3 scale). *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 **407** lies in a disulfide bond; a β-strand.

AlphaFold model confidence (whole protein): pLDDT 90.58, 72% of residues very-high.

**1 experimental structure(s)** (PDB): [4ZEL](https://www.rcsb.org/structure/4ZEL).

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

*Describes the biological roles of DBH (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:** DBH's established molecular role includes dopamine beta-monooxygenase activity.


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Catecholamine biosynthesis](https://reactome.org/content/detail/R-HSA-209905) | curated |

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

**Molecular function:** dopamine beta-monooxygenase activity, copper ion binding.

**Biological process:** dopamine catabolic process, norepinephrine biosynthetic process.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-11-23.

**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 | 2022-11-23 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases.

## Similar variants {#similar}

Related DBH variant pages (same residue, condition, or type): [DBH p.Phe407=](/variant/dbh-p-phe407), [DBH p.Ala113Ser](/variant/dbh-p-ala113ser), [DBH p.Ala383Val](/variant/dbh-p-ala383val), [DBH p.Arg43His](/variant/dbh-p-arg43his), [DBH p.Arg473Gln](/variant/dbh-p-arg473gln), [DBH p.Arg549Leu](/variant/dbh-p-arg549leu), [DBH p.Arg572His](/variant/dbh-p-arg572his), [DBH p.Arg6His](/variant/dbh-p-arg6his).

### 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 2386226). 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.*