Is PCBD1 p.Leu55= (c.165G>A) pathogenic?

PCBD1 p.Leu55= (c.165G>A) is classified Likely benign in PCBD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-10). Very rare (popmax 0.0011%, sas); Associated with pterin-4 alpha-carbinolamine dehydratase 1 deficiency.

What condition is associated with PCBD1 p.Leu55= (c.165G>A)?

PCBD1 p.Leu55= (c.165G>A) is associated with pterin-4 alpha-carbinolamine dehydratase 1 deficiency (ClinVar).

How common is PCBD1 p.Leu55= (c.165G>A) in the general population?

PCBD1 p.Leu55= (c.165G>A) is very rare (popmax 0.0011%, sas) (gnomAD).

PCBD1 p.Leu55=

Q: How is Hyperphenylalaninemia due to tetrahydrobiopterin deficiency inherited?

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

c.165G>A · rs1272848287 · VCV2920299

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

pterin-4 alpha-carbinolamine dehydratase 1 deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.074	GERP -1.6, phastCons 0.52
Overall
CADD	9.725	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,068 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000434% 7/1,614,060 alleles · very rare exomes 7/1,461,760 · genomes 0/152,300 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,496
South Asiangrpmax	0.0011%	91,068
European (non-Finnish)	0.000424%	235,992

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: PCBD1
Protein: p.Leu55=
Coding: c.165G>A
MANE Select: NM_000281
dbSNP: rs1272848287
Type: single nucleotide variant
Location: chr10:70885203 (GRCh38)
Gene constraint: LOEUF 1.685 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.55
Residue 55: a UniProt-annotated variant site (in hpabh4d; reduced protein levels; loss of hnf1b interaction; loss of hnf1b-coactivator activity)

Full PCBD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

pterin-4 alpha-carbinolamine dehydratase 1 deficiency — 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

PCBD1 p.Gln98Ter Pathogenic/Likely pathogenic ★★ same condition
PCBD1 p.Glu87Ter Pathogenic/Likely pathogenic ★★ same condition
PCBD1 p.Glu97Lys Pathogenic/Likely pathogenic ★★ same condition
PCBD1 p.Arg13Trp Uncertain significance ★★ ⚠ same condition
PCBD1 p.Arg31Cys Uncertain significance ★★ ⚠ same condition
PCBD1 p.Arg88Trp Uncertain significance ★★ ⚠ same condition
PCBD1 p.Asp61Tyr Uncertain significance ★★ ⚠ same condition
PCBD1 p.Gln15His Uncertain significance ★★ ⚠ 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/pcbd1-p-leu55 (accessed [today's date]).

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