Is PTS p.Ala83= (c.249G>A) pathogenic?

PTS p.Ala83= (c.249G>A) is classified Likely benign in PTS (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-26). Very rare (popmax 0.00329%, sas); Associated with BH4-deficient hyperphenylalaninemia A.

What condition is associated with PTS p.Ala83= (c.249G>A)?

PTS p.Ala83= (c.249G>A) is associated with BH4-deficient hyperphenylalaninemia A (ClinVar).

How common is PTS p.Ala83= (c.249G>A) in the general population?

PTS p.Ala83= (c.249G>A) is very rare (popmax 0.00329%, sas) (gnomAD).

PTS p.Ala83=

Q: How is Hyperphenylalaninemia due to tetrahydrobiopterin deficiency inherited?

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

c.249G>A · rs760485224 · VCV1927252

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Conditions

BH4-deficient hyperphenylalaninemia A

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.335	indeterminate
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.67	GERP -4
Overall
CADD	7.014	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00329% South Asian · 3/91,058 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000558% 9/1,613,706 alleles · very rare exomes 7/1,461,542 · genomes 2/152,164 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00329%	30,353
East Asian	0.00223%	44,886
Finnishnot grpmax-eligible	0.00156%	64,034
African / African-American	0.00133%	74,914
European (non-Finnish)	0.000254%	393,247

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.Ala83=
Coding: c.249G>A
MANE Select: NM_000317
dbSNP: rs760485224
Type: single nucleotide variant
Location: chr11:112233168 (GRCh38)
Gene constraint: LOEUF 1.695 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.01 · 1 PDB
Residue 83: 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.Ala83Glu Conflicting classifications of pathogenicity ★ ⚠ 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-ala83 (accessed [today's date]).

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