# NM_000379.4(XDH):c.1662C>T (p.Pro554=)

https://sugi.bio/variant/xdh-p-pro554

## Summary

**XDH p.Pro554= (c.1662C>T)** is classified **Likely benign** in XDH (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-08). Very rare (popmax 0.00549%, sas); Associated with xanthinuria type II.

**At a glance:** Likely benign · review: Single submitter · rsID rs561567798 · 1 submitter · 1 linked condition · very rare (popmax 0.00549%, sas)

## For patients & families {#patients}

This is a change in the XDH gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to xanthinuria type II.

*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) | All ages |
| Diagnostic panels | XDH is a diagnostic-grade gene on 2 Genomics England panels |

**Commonly reported features of Hereditary xanthinuria** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Hypouricemia — Very frequent (99-80%)
- Decreased urinary urate — Very frequent (99-80%)
- Uric acid nephrolithiasis — Frequent (79-30%)
- Xanthine nephrolithiasis — Frequent (79-30%)
- Aldehyde oxidase deficiency — Frequent (79-30%)
- Reduced xanthine dehydrogenase activity — Frequent (79-30%)
- Sulfite oxidase deficiency — Frequent (79-30%)
- Hyperxanthinemia — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0005620/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [XDH](https://sugi.bio/atlas/gene/XDH/) |
| Protein change (HGVS p.) | p.Pro554= |
| Coding change (HGVS c.) | c.1662C>T |
| MANE Select transcript | [NM_003104](https://www.ncbi.nlm.nih.gov/nuccore/NM_003104) (variant reported on NM_000379) |
| dbSNP | [rs561567798](https://www.ncbi.nlm.nih.gov/snp/rs561567798/) |
| Variant type | single nucleotide variant |
| Location | chr2:31373897-31373897 (GRCh38) |
| ClinVar | [VCV3012368](https://www.ncbi.nlm.nih.gov/clinvar/variation/3012368/) |

**All HGVS expressions:** `NC_000002.11:g.31596763G>A`, `NC_000002.12:g.31373897G>A`, `NG_008871.2:g.45849C>T`, `NM_000379.4:c.1662C>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 1.11, GERP -3.21, phastCons 0.996 — weakly conserved position
- CADD: **PHRED 0.794**. 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: **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 (gnomAD v4.1): grpmax **0.00549%** (sas) · FAF95 0.00211% · FAF99 0.00136% · 5/91,036 in the highest group · 5/1,613,910 alleles overall — very rare (popmax 0.00549%, sas).

*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}

**XDH** population constraint: ClinGen dosage — haploinsufficiency 30, triplosensitivity 0 (0–3 scale). *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):

- **Charcot-Marie-Tooth disease** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 98.06, 98% of residues very-high.

**3 experimental structure(s)** (PDB): [1PL6](https://www.rcsb.org/structure/1PL6), [1PL7](https://www.rcsb.org/structure/1PL7), [1PL8](https://www.rcsb.org/structure/1PL8).

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

*Describes the biological roles of XDH (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:** XDH's established molecular role includes L-iditol 2-dehydrogenase (NAD+) activity.


### Pathways affected {#pathways}

XDH participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Formation of xylulose-5-phosphate](https://reactome.org/content/detail/R-HSA-5661270) | curated |
| [Fructose biosynthesis](https://reactome.org/content/detail/R-HSA-5652227) | curated |

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

**Molecular function:** L-iditol 2-dehydrogenase (NAD+) activity, zinc ion binding, identical protein binding, NAD binding.

**Biological process:** D-sorbitol catabolic process, fructose biosynthetic process, xylitol catabolic process, xylitol metabolic process.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-12-08.

**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 | 2025-12-08 |

## Associated conditions {#conditions}

[xanthinuria type II](https://sugi.bio/atlas/disease/xanthinuria-type-ii/).

**Reported phenotype names (ClinVar):** Xanthinuria type II, Xanthine dehydrogenase and aldehyde oxidase combined deficiency of, XDH and AOX dual deficiency.

## Similar variants {#similar}

Related XDH variant pages (same residue, condition, or type): [XDH p.Pro554Leu](/variant/xdh-p-pro554leu), [XDH c.1602+1G>A](/variant/xdh-c-1602-plus-1g-a), [XDH c.565-1G>A](/variant/xdh-c-565-minus-1g-a), [XDH p.Arg1283Ter](/variant/xdh-p-arg1283ter), [XDH p.Arg228Ter](/variant/xdh-p-arg228ter), [XDH p.Arg825Ter](/variant/xdh-p-arg825ter), [XDH p.Gln251Ter](/variant/xdh-p-gln251ter), [XDH p.Lys722Ter](/variant/xdh-p-lys722ter).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2026-07-14); 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 3012368). 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.*