Is PTS p.Val104= (c.312G>A) pathogenic?

PTS p.Val104= (c.312G>A) is classified Conflicting classifications of pathogenicity in PTS (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-06-01). Ultra-rare (popmax 0.0242%, sas); Associated with BH4-deficient hyperphenylalaninemia A.

What condition is associated with PTS p.Val104= (c.312G>A)?

PTS p.Val104= (c.312G>A) is associated with BH4-deficient hyperphenylalaninemia A (ClinVar).

How common is PTS p.Val104= (c.312G>A) in the general population?

PTS p.Val104= (c.312G>A) is ultra-rare (popmax 0.0242%, sas) (gnomAD).

PTS p.Val104=

Q: How is Hyperphenylalaninemia due to tetrahydrobiopterin deficiency inherited?

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

c.312G>A · rs148185068 · VCV1144715

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0242%, sas)

Conditions

BH4-deficient hyperphenylalaninemia A

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.60	donor gain · deltas
Pangolin	Δ0.52	gain · loss 0.18 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP -0.57	GERP -4
Overall
CADD	12.63	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0242% South Asian · 22/91,066 alleles

Filtering AF 0.0163% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0138%

Overall 0.00298% 48/1,613,432 alleles · ultra-rare exomes 46/1,461,232 · genomes 2/152,200 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0242%	4,139
Middle Eastern	0.0164%	6,080
European (non-Finnish)	0.00203%	49,145
Remaining individualsnot grpmax-eligible	0.0016%	62,460

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.Val104=
Coding: c.312G>A
MANE Select: NM_000317
dbSNP: rs148185068
Type: single nucleotide variant
Location: chr11:112233231 (GRCh38)
Gene constraint: LOEUF 1.695 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.01 · 1 PDB

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 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
PTS c.84-2A>G 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-val104 (accessed [today's date]).

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