# NM_000281.4(PCBD1):c.5C>T (p.Ala2Val)

https://sugi.bio/variant/pcbd1-p-ala2val

## Summary

**PCBD1 p.Ala2Val (c.5C>T)** is classified **Uncertain significance** in PCBD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-02-15). AlphaMissense: likely benign (0.2627); Absent from gnomAD v4.1; Associated with pterin-4 alpha-carbinolamine dehydratase 1 deficiency.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1846575724 · 1 submitter · 1 linked condition · AlphaMissense likely benign · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the PCBD1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, 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.Ala2Val |
| Coding change (HGVS c.) | c.5C>T |
| MANE Select transcript | [NM_000281](https://www.ncbi.nlm.nih.gov/nuccore/NM_000281) |
| dbSNP | [rs1846575724](https://www.ncbi.nlm.nih.gov/snp/rs1846575724/) |
| Variant type | single nucleotide variant |
| Location | chr10:70885928-70885928 (GRCh38) |
| ClinVar | [VCV1372630](https://www.ncbi.nlm.nih.gov/clinvar/variation/1372630/) |

**All HGVS expressions:** `NC_000010.10:g.72645685G>A`, `NC_000010.11:g.70885928G>A`, `NG_008646.1:g.7857C>T`, `NM_000281.4:c.5C>T`, `NM_001289797.2:c.-143C>T`, `NM_001323004.2:c.5C>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.2627)
- REVEL 0.4 (indeterminate)
- SaProt LLR -8.103 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate
- Conservation: phyloP 11.722, GERP 0.786, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 26.6**. 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.*
- Regional missense constraint: **o/e 0.66** across the covering region of the MANE Select transcript (70,883,953–70,888,533), spanning 4,580 bp. Chi-square p 0.00011. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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 **2** lies in a modified residue (n-acetylalanine).

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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-02-15.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-02-15 |

## 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 WITH PRIMAPTERINURIA, HYPERPHENYLALANINEMIA, TETRAHYDROBIOPTERIN-DEFICIENT, DUE TO PTERIN-4-ALPHA-CARBINOLAMINE DEHYDRATASE DEFICIENCY, Hyperphenylalaninemia due to dehydratase deficiency, CADH DEFICIENCY.

## Similar variants {#similar}

Related PCBD1 variant pages (same residue, condition, or type): [PCBD1 p.Ala2Asp](/variant/pcbd1-p-ala2asp), [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).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 1372630). 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.*