Is PCBD1 p.Gln98= (c.294A>G) pathogenic?

PCBD1 p.Gln98= (c.294A>G) is classified Conflicting classifications of pathogenicity in PCBD1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-06-19). Ultra-rare (popmax 0.0178%, eas); Associated with pterin-4 alpha-carbinolamine dehydratase 1 deficiency.

What condition is associated with PCBD1 p.Gln98= (c.294A>G)?

PCBD1 p.Gln98= (c.294A>G) is associated with pterin-4 alpha-carbinolamine dehydratase 1 deficiency (ClinVar).

How common is PCBD1 p.Gln98= (c.294A>G) in the general population?

PCBD1 p.Gln98= (c.294A>G) is ultra-rare (popmax 0.0178%, eas) (gnomAD).

PCBD1 p.Gln98=

Q: How is Hyperphenylalaninemia due to tetrahydrobiopterin deficiency inherited?

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

c.294A>G · rs773744136 · VCV1508980

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0178%, eas)

Conditions

pterin-4 alpha-carbinolamine dehydratase 1 deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.20	donor gain · deltas
Pangolin	Δ0.81	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 5	GERP 1.9, phastCons 1
Overall
CADD	15.06	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0178% East Asian · 8/44,904 alleles

Filtering AF 0.00883% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00641%

Overall 0.00062% 10/1,613,942 alleles · ultra-rare exomes 9/1,461,742 · genomes 1/152,200 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0178%	5,613
Remaining individualsnot grpmax-eligible	0.0016%	62,486
European (non-Finnish)	8.47e-05%	1,179,998

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.Gln98=
Coding: c.294A>G
MANE Select: NM_000281
dbSNP: rs773744136
Type: single nucleotide variant
Location: chr10:70883971 (GRCh38)
Gene constraint: LOEUF 1.685 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.55
Residue 98: a UniProt-annotated variant site (in hpabh4d; increased proteolytic degradation; loss of hnf1b interaction; loss of hnf1b-coactivator activity); 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 residue
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-gln98 (accessed [today's date]).

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