Is QDPR p.Pro204fs (c.609dup) pathogenic?

QDPR p.Pro204fs (c.609dup) is classified Pathogenic/Likely pathogenic in QDPR (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-01-05). Very rare (popmax 0.000339%, nfe); Associated with dihydropteridine reductase deficiency.

What condition is associated with QDPR p.Pro204fs (c.609dup)?

QDPR p.Pro204fs (c.609dup) is associated with dihydropteridine reductase deficiency (ClinVar).

How common is QDPR p.Pro204fs (c.609dup) in the general population?

QDPR p.Pro204fs (c.609dup) is very rare (popmax 0.000339%, nfe) (gnomAD).

QDPR p.Pro204fs

Q: How is Hyperphenylalaninemia due to tetrahydrobiopterin deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.609dup · rs769289876 · VCV2734651

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Conditions

dihydropteridine reductase deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon within the last 50 nt of the penultimate exon (6 of 7, 19 nt from its 3' end) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 12	GERP 2.2, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000339% European (non-Finnish) · 4/1,179,776 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.00031% 5/1,613,868 alleles · very rare exomes 5/1,461,572 · genomes 0/152,296 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,504
European (non-Finnish)grpmax	0.000339%	294,944

Remaining individuals shows a higher raw frequency than the grpmax group above it. 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.

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: QDPR
Protein: p.Pro204fs
Coding: c.609dup
MANE Select: NM_000320
dbSNP: rs769289876
Type: Duplication
Location: chr4:17490681 (GRCh38)
Gene constraint: LOEUF 0.984 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.43 · 2 PDB

Full QDPR gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

dihydropteridine reductase deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hyperphenylalaninemia due to tetrahydrobiopterin deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal
Prevalence: 1-9 / 1 000 000 (Japan)

Similar variants

QDPR p.Pro204= Likely benign ★ same residue
QDPR p.Ile216_Gly218dup Uncertain significance ★★ same condition
QDPR c.545+2dup Uncertain significance ★ same condition
QDPR p.Ala140_Leu141insProLysAlaAla Uncertain significance ★ same condition
QDPR c.199-16dup Benign ★ same condition
QDPR c.296-8dup Benign ★ same condition
QDPR c.630-20dup Benign ★ same condition
QDPR p.Thr123dup Pathogenic same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/qdpr-p-pro204fs (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown