Is PTS p.Pro87Ser (c.259C>T) pathogenic?

PTS p.Pro87Ser (c.259C>T) is classified Pathogenic in PTS (ClinVar, Multiple submitters, 11 submitters; last evaluated 2026-01-09). AlphaMissense: likely benign (0.306); Ultra-rare (popmax 0.0535%, eas); Associated with hyperphenylalaninemia due to tetrahydrobiopterin deficiency.

What condition is associated with PTS p.Pro87Ser (c.259C>T)?

PTS p.Pro87Ser (c.259C>T) is associated with hyperphenylalaninemia due to tetrahydrobiopterin deficiency, BH4-deficient hyperphenylalaninemia A, GTP cyclohydrolase I deficiency with hyperphenylalaninemia (ClinVar).

How common is PTS p.Pro87Ser (c.259C>T) in the general population?

PTS p.Pro87Ser (c.259C>T) is ultra-rare (popmax 0.0535%, eas) (gnomAD).

What do computational predictors say about PTS p.Pro87Ser (c.259C>T)?

AlphaMissense predicts likely benign (score 0.306) — an in-silico prediction, not a clinical call.

PTS p.Pro87Ser

Q: How is Hyperphenylalaninemia due to tetrahydrobiopterin deficiency inherited?

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

c.259C>T · rs104894276 · VCV480

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

AlphaMissense

likely benign

0.306 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0535%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hyperphenylalaninemia due to tetrahydrobiopterin deficiency

Computational evidence

Protein change
AlphaMissense	0.306	likely benign ⚠ discordant with ClinVar
REVEL	0.855	moderately pathogenic-leaning
SaProt	LLR -11.38	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 7,108 bp · p 0.79 · regional, not allelic
Overall
CADD	24.9	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0535% East Asian · 24/44,878 alleles

Filtering AF 0.0368% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0313%

Overall 0.00173% 28/1,613,918 alleles · ultra-rare exomes 26/1,461,688 · genomes 2/152,230 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0535%	1,870
Remaining individualsnot grpmax-eligible	0.0016%	62,496
European (non-Finnish)	0.000254%	393,287

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: PTS
Protein: p.Pro87Ser
Coding: c.259C>T
MANE Select: NM_000317
dbSNP: rs104894276
Type: single nucleotide variant
Location: chr11:112233178 (GRCh38)
Gene constraint: LOEUF 1.695 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.01 · 1 PDB
Residue 87: a UniProt-annotated variant site (in hpabh4a); a UniProt-annotated variant site (in hpabh4a; severe form)

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

Disease context

hyperphenylalaninemia due to tetrahydrobiopterin deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: BH4-deficient hyperphenylalaninemia A GTP cyclohydrolase I deficiency with hyperphenylalaninemia

For Hyperphenylalaninemia due to tetrahydrobiopterin deficiency (Orphanet):

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

Similar variants

PTS p.Pro87Leu Pathogenic ★★ ⚠ same residue
PTS p.Pro87= Likely benign ★ same residue
PTS c.186+1G>A Pathogenic ★★ same condition
PTS c.186+1G>T Pathogenic ★★ same condition
PTS c.187-2A>G Likely pathogenic ★★ same condition
PTS c.315-1G>A Pathogenic/Likely pathogenic ★★ same condition
PTS c.315-2A>G Pathogenic/Likely pathogenic ★★ same condition
PTS c.84-1G>A 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-pro87ser (accessed [today's date]).

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