Is PCBD1 p.Cys82= (c.246T>C) pathogenic?

PCBD1 p.Cys82= (c.246T>C) is classified Likely benign in PCBD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-05). Very rare (popmax 0.00754%, nfe); Associated with pterin-4 alpha-carbinolamine dehydratase 1 deficiency.

What condition is associated with PCBD1 p.Cys82= (c.246T>C)?

PCBD1 p.Cys82= (c.246T>C) is associated with pterin-4 alpha-carbinolamine dehydratase 1 deficiency (ClinVar).

How common is PCBD1 p.Cys82= (c.246T>C) in the general population?

PCBD1 p.Cys82= (c.246T>C) is very rare (popmax 0.00754%, nfe) (gnomAD).

PCBD1 p.Cys82=

Q: How is Hyperphenylalaninemia due to tetrahydrobiopterin deficiency inherited?

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

c.246T>C · rs371676743 · VCV1574898

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00754%, nfe)

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 2.3	GERP 1.9, phastCons 1
Overall
CADD	11.94	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00754% European (non-Finnish) · 89/1,180,018 alleles

Filtering AF 0.00623% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00579%

Overall 0.00576% 93/1,614,012 alleles · very rare exomes 88/1,461,790 · genomes 5/152,222 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00754%	13,259
African / African-American	0.00267%	37,470
Remaining individualsnot grpmax-eligible	0.0016%	62,486
Finnishnot grpmax-eligible	0.00156%	64,026

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.Cys82=
Coding: c.246T>C
MANE Select: NM_000281
dbSNP: rs371676743
Type: single nucleotide variant
Location: chr10:70884019 (GRCh38)
Gene constraint: LOEUF 1.685 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.55
Residue 82: a UniProt-annotated variant site (in hpabh4d; reduced protein levels; loss of hnf1b interaction; loss of hnf1b-coactivator activity); a UniProt-annotated variant site (in hpabh4d; increased proteolytic degradation; reduced dehydratase activity; no impact on hydroxytetrahydrobiopterin-binding; reduced interaction with hnf1b; partial impact on 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.Cys82Arg Likely pathogenic ★ same residue
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

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-cys82 (accessed [today's date]).

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