Is QDPR p.Val40Ile (c.118G>A) pathogenic?

QDPR p.Val40Ile (c.118G>A) is classified Uncertain significance in QDPR (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-07-08). AlphaMissense: likely benign (0.0744); Ultra-rare (popmax 0.0165%, mid); Associated with dihydropteridine reductase deficiency.

What condition is associated with QDPR p.Val40Ile (c.118G>A)?

QDPR p.Val40Ile (c.118G>A) is associated with dihydropteridine reductase deficiency (ClinVar).

How common is QDPR p.Val40Ile (c.118G>A) in the general population?

QDPR p.Val40Ile (c.118G>A) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about QDPR p.Val40Ile (c.118G>A)?

AlphaMissense predicts likely benign (score 0.0744) — an in-silico prediction, not a clinical call.

QDPR p.Val40Ile

Q: How is Hyperphenylalaninemia due to tetrahydrobiopterin deficiency inherited?

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

c.118G>A · rs769586091 · VCV1030732

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0744 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

dihydropteridine reductase deficiency

Computational evidence

Protein change
AlphaMissense	0.0744	likely benign
REVEL	0.353	indeterminate
SaProt	LLR -7.99	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 1.3, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 25 kb · p 0.99 · regional, not allelic
Overall
CADD	18.47	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,060 alleles

Filtering AF 0.00514% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00375%

Overall 0.00161% 26/1,613,750 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,060
South Asian	0.00988%	10,120
Remaining individualsnot grpmax-eligible	0.0016%	62,482
European (non-Finnish)	0.00127%	78,650

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.Val40Ile
Coding: c.118G>A
MANE Select: NM_000320
dbSNP: rs769586091
Type: single nucleotide variant
Location: chr4:17509351 (GRCh38)
Gene constraint: LOEUF 0.984 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.43 · 2 PDB
Residue 40: a β-strand

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 c.436+2552A>G Pathogenic ★★ same condition
QDPR c.545+1G>A Pathogenic ★★ same condition
QDPR c.546-1G>A Likely pathogenic ★★ same condition
QDPR p.Arg221Ter Pathogenic ★★ same condition
QDPR p.His158Tyr Pathogenic/Likely pathogenic ★★ same condition
QDPR p.Phe212Ser Likely pathogenic ★★ same condition
QDPR p.Ser115Leu Pathogenic/Likely pathogenic ★★ same condition
QDPR p.Tyr150Cys 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-val40ile (accessed [today's date]).

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