# NM_000281.4(PCBD1):c.249C>T (p.Ala83=)

https://sugi.bio/variant/pcbd1-p-ala83

## Summary

**PCBD1 p.Ala83= (c.249C>T)** is classified **Likely benign** in PCBD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-13). Ultra-rare (popmax 0.0178%, eas); Associated with pterin-4 alpha-carbinolamine dehydratase 1 deficiency.

**At a glance:** Likely benign · review: Single submitter · rsID rs148217100 · 1 submitter · 1 linked condition · ultra-rare (popmax 0.0178%, eas)

## For patients & families {#patients}

This is a change in the PCBD1 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to pterin-4 alpha-carbinolamine dehydratase 1 deficiency.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Infancy, Neonatal |
| Prevalence | 1-9 / 1 000 000 (Japan) |
| Diagnostic panels | PCBD1 is a diagnostic-grade gene on 9 Genomics England panels |

**Commonly reported features of Hyperphenylalaninemia due to tetrahydrobiopterin deficiency** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Hyperphenylalaninemia — Very frequent (99-80%)
- Atypical behavior — Frequent (79-30%)
- Hypotonia — Frequent (79-30%)
- Excessive salivation — Frequent (79-30%)
- Decreased CSF homovanillic acid concentration — Frequent (79-30%)
- Neurodevelopmental delay — Frequent (79-30%)
- Abnormal circulating neopterin concentration — Frequent (79-30%)
- Abnormal circulating biopterin concentration — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0002843/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PCBD1](https://sugi.bio/atlas/gene/PCBD1/) |
| Protein change (HGVS p.) | p.Ala83= |
| Coding change (HGVS c.) | c.249C>T |
| MANE Select transcript | [NM_000281](https://www.ncbi.nlm.nih.gov/nuccore/NM_000281) |
| dbSNP | [rs148217100](https://www.ncbi.nlm.nih.gov/snp/rs148217100/) |
| Variant type | single nucleotide variant |
| Location | chr10:70884016-70884016 (GRCh38) |
| ClinVar | [VCV751908](https://www.ncbi.nlm.nih.gov/clinvar/variation/751908/) |

**All HGVS expressions:** `NC_000010.10:g.72643773G>A`, `NC_000010.11:g.70884016G>A`, `NG_008646.1:g.9769C>T`, `NM_000281.4:c.249C>T`, `NM_001289797.2:c.102C>T`, `NM_001323004.2:c.216+1136C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP -14.913, GERP -3.89 — fast-evolving / accelerated position
- CADD: **PHRED 0.376**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for PCBD1 (226 scored positions, the nearest 33 bases away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency (gnomAD v4.1): grpmax **0.0178%** (eas) · FAF95 0.00884% · FAF99 0.00641% · 8/44,880 in the highest group · 38/1,614,050 alleles overall — ultra-rare (popmax 0.0178%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.0178% | 5,610 |
| European (non-Finnish) | 0.00229% | 43,703 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,508 |
| African / African-American | 0.00133% | 75,022 |
| South Asian | 0.0011% | 91,032 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**PCBD1** population constraint: LOEUF 1.685, pLI 1.3794e-05, missense-Z 1.5951. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **pterin-4 alpha-carbinolamine dehydratase 1 deficiency** — Definitive (AR)

## Protein context {#protein}

Residue **83** lies in a UniProt-annotated variant site (in hpabh4d; reduced protein levels; loss of hnf1b interaction; loss of hnf1b-coactivator activity).

AlphaFold model confidence (whole protein): pLDDT 96.55, 95% of residues very-high.

## What this gene does {#gene-function}

*Describes the biological roles of PCBD1 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** PCBD1's established molecular role includes identical protein binding.


### Pathways affected {#pathways}

PCBD1 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Phenylalanine metabolism](https://reactome.org/content/detail/R-HSA-8964208) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** identical protein binding.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-03-13.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-03-13 |

## Associated conditions {#conditions}

[pterin-4 alpha-carbinolamine dehydratase 1 deficiency](https://sugi.bio/atlas/disease/pterin-4-alpha-carbinolamine-dehydratase-1-deficiency/).

**Reported phenotype names (ClinVar):** Pterin-4 alpha-carbinolamine dehydratase 1 deficiency, Hyperphenylalaninemia due to dehydratase deficiency, CADH DEFICIENCY, HYPERPHENYLALANINEMIA WITH PRIMAPTERINURIA, HYPERPHENYLALANINEMIA, TETRAHYDROBIOPTERIN-DEFICIENT, DUE TO PTERIN-4-ALPHA-CARBINOLAMINE DEHYDRATASE DEFICIENCY.

## Similar variants {#similar}

Related PCBD1 variant pages (same residue, condition, or type): [PCBD1 p.Gln98Ter](/variant/pcbd1-p-gln98ter), [PCBD1 p.Glu87Ter](/variant/pcbd1-p-glu87ter), [PCBD1 p.Glu97Lys](/variant/pcbd1-p-glu97lys), [PCBD1 p.Arg13Trp](/variant/pcbd1-p-arg13trp), [PCBD1 p.Arg31Cys](/variant/pcbd1-p-arg31cys), [PCBD1 p.Arg88Trp](/variant/pcbd1-p-arg88trp), [PCBD1 p.Asp61Tyr](/variant/pcbd1-p-asp61tyr), [PCBD1 p.Gln15His](/variant/pcbd1-p-gln15his).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 751908). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*