# NM_000320.3(QDPR):c.661C>T (p.Arg221Ter)

https://sugi.bio/variant/qdpr-p-arg221ter

## Summary

**QDPR p.Arg221Ter (c.661C>T)** is classified **Pathogenic** in QDPR (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-06). Very rare (popmax 0.00167%, amr); Associated with dihydropteridine reductase deficiency.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs779997983 · 4 submitters · 1 linked condition · very rare (popmax 0.00167%, amr)

## For patients & families {#patients}

This is a change in the QDPR gene that is considered disease-causing, submitted by 4 submitters, and is linked to dihydropteridine reductase deficiency.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Infancy, Neonatal |
| Prevalence | 1-9 / 1 000 000 (Japan) |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | QDPR is a diagnostic-grade gene on 8 Genomics England panels |

**Commonly reported features of Hyperphenylalaninemia due to tetrahydrobiopterin deficiency** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Hyperphenylalaninemia — Very frequent (99-80%)
- Atypical behavior — Frequent (79-30%)
- Hypotonia — Frequent (79-30%)
- Excessive salivation — Frequent (79-30%)
- Decreased CSF homovanillic acid concentration — Frequent (79-30%)
- Neurodevelopmental delay — Frequent (79-30%)
- Abnormal circulating neopterin concentration — Frequent (79-30%)
- Abnormal circulating biopterin concentration — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0004319/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [QDPR](https://sugi.bio/atlas/gene/QDPR/) |
| Protein change (HGVS p.) | p.Arg221Ter |
| Coding change (HGVS c.) | c.661C>T |
| MANE Select transcript | [NM_000320](https://www.ncbi.nlm.nih.gov/nuccore/NM_000320) |
| dbSNP | [rs779997983](https://www.ncbi.nlm.nih.gov/snp/rs779997983/) |
| Variant type | single nucleotide variant |
| Location | chr4:17487205-17487205 (GRCh38) |
| ClinVar | [VCV802058](https://www.ncbi.nlm.nih.gov/clinvar/variation/802058/) |

**All HGVS expressions:** `NC_000004.11:g.17488828G>A`, `NC_000004.12:g.17487205G>A`, `NG_008763.1:g.30030C>T`, `NM_000320.3:c.661C>T`, `NM_001306140.2:c.568C>T`, `NR_156494.2:n.588C>T`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 6.01, GERP 0.489, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **nonsense (stop-gain)** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.984, pLI 4.011e-06. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in the last exon (7 of 7)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- CADD: **PHRED 43.0**. 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.*
- 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.
- Pangolin: Δ**0.24** (loss), gain 0.00 / loss 0.24. Not in the SpliceAI release. 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 **0.00167%** (amr) · FAF95 0.000292% · FAF99 0.000211% · 1/59,996 in the highest group · 10/1,613,970 alleles overall — very rare (popmax 0.00167%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00167% | 59,996 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,488 |
| European (non-Finnish) | 0.000678% | 147,502 |

*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}

**QDPR** population constraint: LOEUF 0.984, pLI 4.011e-06, missense-Z 0.32789. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **dihydropteridine reductase deficiency** — Definitive (AR)

## Protein context {#protein}

Residue **221** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 96.43, 96% of residues very-high.

**2 experimental structure(s)** (PDB): [1HDR](https://www.rcsb.org/structure/1HDR), [9DTW](https://www.rcsb.org/structure/9DTW).

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

*Describes the biological roles of QDPR (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:** QDPR's established molecular role includes 6,7-dihydropteridine reductase activity.


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Phenylalanine metabolism](https://reactome.org/content/detail/R-HSA-8964208) | curated |

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

**Molecular function:** 6,7-dihydropteridine reductase activity.

## Clinical significance {#significance}

**Pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-06.

**Submitter consensus:** unanimous (4/4 Pathogenic).

**Submission history:** 4 submissions (2019–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Mendelics | Pathogenic | criteria provided, single submitter | clinical testing | 2019-05-28 |
| Fulgent Genetics, Fulgent Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2024-05-01 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-11-24 |
| Dasa | Pathogenic | criteria provided, single submitter | clinical testing | 2026-02-06 |

## Associated conditions {#conditions}

[dihydropteridine reductase deficiency](https://sugi.bio/atlas/disease/dihydropteridine-reductase-deficiency/).

**Reported phenotype names (ClinVar):** Dihydropteridine reductase deficiency, not provided, none provided, BH4-Deficient Hyperphenylalaninemia C, Phenylketonuria II, Hyperphenylalaninemia due to dihydropteridine reductase deficiency, Hyperphenylalaninemia, BH-4-deficient, C, Phenylketonuria type 2, DHPR DEFICIENCY, HYPERPHENYLALANINEMIA, TETRAHYDROBIOPTERIN-DEFICIENT, DUE TO DHPR DEFICIENCY.

## Similar variants {#similar}

Related QDPR variant pages (same residue, condition, or type): [QDPR p.Arg221Gln](/variant/qdpr-p-arg221gln), [QDPR c.436+2552A>G](/variant/qdpr-c-436-plus-2552a-g), [QDPR c.545+1G>A](/variant/qdpr-c-545-plus-1g-a), [QDPR c.546-1G>A](/variant/qdpr-c-546-minus-1g-a), [QDPR p.His158Tyr](/variant/qdpr-p-his158tyr), [QDPR p.Phe212Ser](/variant/qdpr-p-phe212ser), [QDPR p.Ser115Leu](/variant/qdpr-p-ser115leu), [QDPR p.Tyr150Cys](/variant/qdpr-p-tyr150cys).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 802058). 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.*