Is PTS p.Phe40fs (c.118_121del) pathogenic?

PTS p.Phe40fs (c.118121del) is classified Pathogenic in PTS (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-06-04). Very rare (popmax 0.00226%, eas); Associated with BH4-deficient hyperphenylalaninemia A.

What condition is associated with PTS p.Phe40fs (c.118_121del)?

PTS p.Phe40fs (c.118_121del) is associated with BH4-deficient hyperphenylalaninemia A (ClinVar).

How common is PTS p.Phe40fs (c.118_121del) in the general population?

PTS p.Phe40fs (c.118_121del) is very rare (popmax 0.00226%, eas) (gnomAD).

PTS p.Phe40fs

Q: How is Hyperphenylalaninemia due to tetrahydrobiopterin deficiency inherited?

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

c.118_121del · rs747260038 · VCV550850

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00226%, eas)

Conditions

BH4-deficient hyperphenylalaninemia A

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 2 of 6
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.58	GERP -1.5, phastCons 0.36
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00226% East Asian · 1/44,330 alleles

Filtering AF 0.000125% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.1e-05%

Overall 0.000439% 7/1,595,816 alleles · very rare exomes 6/1,449,290 · genomes 1/146,526 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00226%	44,330
South Asian	0.00111%	90,276
European (non-Finnish)	0.000427%	234,415

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.Phe40fs
Coding: c.118_121del
MANE Select: NM_000317
dbSNP: rs747260038
Type: Deletion
Location: chr11:112228626 (GRCh38)
Gene constraint: LOEUF 1.695 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.01 · 1 PDB
Residue 40: 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.Phe40Leu Uncertain significance ★ ⚠ same residue
PTS p.Phe40= Likely benign ★ same residue
PTS p.Val132fs Pathogenic ★★ same condition
PTS p.Val59fs Pathogenic/Likely pathogenic ★★ same condition
PTS p.Val70fs Likely pathogenic ★★ same condition
PTS c.163+696_163+750del Pathogenic ★ same condition
PTS c.164-4_165del Likely pathogenic ★ same condition
PTS p.Asn36fs 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-phe40fs (accessed [today's date]).

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