Is PTS p.Pro98Ser (c.292C>T) pathogenic?

PTS p.Pro98Ser (c.292C>T) is classified Uncertain significance in PTS (ClinVar, Single submitter, 1 submitter; last evaluated 2021-01-29). AlphaMissense: likely benign (0.1425); Very rare (popmax 0.00134%, afr); Associated with BH4-deficient hyperphenylalaninemia A.

What condition is associated with PTS p.Pro98Ser (c.292C>T)?

PTS p.Pro98Ser (c.292C>T) is associated with BH4-deficient hyperphenylalaninemia A (ClinVar).

How common is PTS p.Pro98Ser (c.292C>T) in the general population?

PTS p.Pro98Ser (c.292C>T) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about PTS p.Pro98Ser (c.292C>T)?

AlphaMissense predicts likely benign (score 0.1425) — an in-silico prediction, not a clinical call.

PTS p.Pro98Ser

Q: How is Hyperphenylalaninemia due to tetrahydrobiopterin deficiency inherited?

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

c.292C>T · rs1859964687 · VCV1423368

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1425 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

BH4-deficient hyperphenylalaninemia A

Computational evidence

Protein change
AlphaMissense	0.1425	likely benign
REVEL	0.727	pathogenic-leaning
SaProt	LLR -10.15	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 5.8	GERP 0.22, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 7,108 bp · p 0.79 · regional, not allelic
Overall
CADD	26.2	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 0.00134% African / African-American · 1/74,894 alleles

Overall 6.2e-05% 1/1,613,838 alleles · very rare exomes 0/1,461,766 · genomes 1/152,072 · joint denominator

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.Pro98Ser
Coding: c.292C>T
MANE Select: NM_000317
dbSNP: rs1859964687
Type: single nucleotide variant
Location: chr11:112233211 (GRCh38)
Gene constraint: LOEUF 1.695 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.01 · 1 PDB
Residue 98: an α-helix

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.Pro98Gln Uncertain significance ★ ⚠ same residue
PTS p.Pro98fs Pathogenic ★ 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-pro98ser (accessed [today's date]).

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