Is PTS p.Val70Asp (c.209T>A) pathogenic?

PTS p.Val70Asp (c.209T>A) is classified Conflicting classifications of pathogenicity in PTS (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-08-13). AlphaMissense: likely pathogenic (0.9665); Absent from gnomAD v4.1; Associated with BH4-deficient hyperphenylalaninemia A.

What condition is associated with PTS p.Val70Asp (c.209T>A)?

PTS p.Val70Asp (c.209T>A) is associated with BH4-deficient hyperphenylalaninemia A (ClinVar).

How common is PTS p.Val70Asp (c.209T>A) in the general population?

PTS p.Val70Asp (c.209T>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PTS p.Val70Asp (c.209T>A)?

AlphaMissense predicts likely pathogenic (score 0.9665) — an in-silico prediction, not a clinical call.

PTS p.Val70Asp

Q: How is Hyperphenylalaninemia due to tetrahydrobiopterin deficiency inherited?

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

c.209T>A · rs1592880489 · VCV659949

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9665 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

BH4-deficient hyperphenylalaninemia A

Computational evidence

Protein change
AlphaMissense	0.9665	likely pathogenic · top 6% in PTS
REVEL	0.978	strongly pathogenic-leaning
SaProt	LLR -16.22	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2.1, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 7,108 bp · p 0.79 · regional, not allelic
Overall
CADD	28.4	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PTS
Protein: p.Val70Asp
Coding: c.209T>A
MANE Select: NM_000317
dbSNP: rs1592880489
Type: single nucleotide variant
Location: chr11:112230648 (GRCh38)
Gene constraint: LOEUF 1.695 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.01 · 1 PDB
Residue 70: a UniProt-annotated variant site (in hpabh4a)

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.Val70fs Likely 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
PTS c.84-291A>G Pathogenic/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-val70asp (accessed [today's date]).

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