Is PTS p.Val59fs (c.174_175del) pathogenic?

PTS p.Val59fs (c.174175del) is classified Pathogenic/Likely pathogenic in PTS (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-05-13). Absent from gnomAD; Associated with BH4-deficient hyperphenylalaninemia A.

What condition is associated with PTS p.Val59fs (c.174_175del)?

PTS p.Val59fs (c.174_175del) is associated with BH4-deficient hyperphenylalaninemia A (ClinVar).

How common is PTS p.Val59fs (c.174_175del) in the general population?

PTS p.Val59fs (c.174_175del) is absent from gnomAD (gnomAD).

PTS p.Val59fs

Q: How is Hyperphenylalaninemia due to tetrahydrobiopterin deficiency inherited?

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

c.174_175del · rs2135408968 · VCV1378622

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

BH4-deficient hyperphenylalaninemia A

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 3 of 6
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.7	GERP 2, phastCons 1

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

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: PTS
Protein: p.Val59fs
Coding: c.174_175del
MANE Select: NM_000317
dbSNP: rs2135408968
Type: Deletion
Location: chr11:112230218 (GRCh38)
Gene constraint: LOEUF 1.695 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.01 · 1 PDB
Residue 59: a β-strand

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

Disease context

BH4-deficient hyperphenylalaninemia A — 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

PTS p.Val59= Likely benign ★ same residue
PTS p.Phe40fs Pathogenic ★★ same condition
PTS p.Val132fs Pathogenic ★★ same condition
PTS p.Val70fs Likely pathogenic ★★ same condition
PTS c.163+696_163+750del Pathogenic ★ same condition
PTS c.164-4_165del Likely pathogenic ★ same condition
PTS p.Asn36fs Pathogenic ★ same condition
PTS p.Lys78fs Likely 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/pts-p-val59fs (accessed [today's date]).

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