# NM_002150.3(HPD):c.414G>A (p.Thr138=)

https://sugi.bio/variant/hpd-p-thr138

## Summary

**HPD p.Thr138= (c.414G>A)** is classified **Benign/Likely benign** in HPD (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-02-03). Common (popmax 7.35%, amr) — too common for a highly-penetrant pathogenic allele; Associated with hawkinsinuria.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs140788110 · 7 submitters · 2 linked conditions · common (popmax 7.35%, amr) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the HPD gene that is classified as benign/likely benign — not considered disease-causing, submitted by 7 submitters, and is linked to hawkinsinuria.

*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 dominant |
| Age of onset (of this condition) | Infancy, Neonatal |
| Prevalence | <1 / 1 000 000 (Worldwide) |
| Diagnostic panels | HPD is a diagnostic-grade gene on 8 Genomics England panels |

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

- Failure to thrive — Very frequent (99-80%)
- Metabolic acidosis — Very frequent (99-80%)
- Fine hair — Very frequent (99-80%)
- 4-Hydroxyphenylpyruvic aciduria — Very frequent (99-80%)
- 4-Hydroxyphenylacetic aciduria — Very frequent (99-80%)
- Sparse hair — Very frequent (99-80%)
- Abnormality of tyrosine metabolism — Very frequent (99-80%)
- Hypotonia — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0005668/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [HPD](https://sugi.bio/atlas/gene/HPD/) |
| Protein change (HGVS p.) | p.Thr138= |
| Coding change (HGVS c.) | c.414G>A |
| MANE Select transcript | [NM_002150](https://www.ncbi.nlm.nih.gov/nuccore/NM_002150) |
| dbSNP | [rs140788110](https://www.ncbi.nlm.nih.gov/snp/rs140788110/) |
| Variant type | single nucleotide variant |
| Location | chr12:121854703-121854703 (GRCh38) |
| ClinVar | [VCV307485](https://www.ncbi.nlm.nih.gov/clinvar/variation/307485/) |

**All HGVS expressions:** `NC_000012.11:g.122292609C>T`, `NC_000012.12:g.121854703C>T`, `NG_016461.1:g.38909G>A`, `NM_001171993.2:c.297G>A`, `NM_002150.3:c.414G>A`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 7.35%, amr) — too common for a highly-penetrant pathogenic allele.

- **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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor gain** (Δ 0.24) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 0.117, GERP 1.64, phastCons 0.921 — weakly conserved position
- CADD: **PHRED 21.7**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.04**, acceptor gain **0.00**, donor gain **0.24**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.24**.
- Population frequency (gnomAD v4.1): grpmax **7.35%** (amr) · FAF95 7.17% · FAF99 7.1% · 4,410/59,998 in the highest group · 5,053/1,610,788 alleles overall — common (popmax 7.35%, amr) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 7.35% | 14 |
| East Asian | 0.312% | 320 |
| Remaining individuals (not grpmax-eligible) | 0.282% | 354 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.108% | 925 |
| African / African-American | 0.0774% | 1,293 |
| South Asian | 0.0286% | 3,500 |
| European (non-Finnish) | 0.0178% | 5,605 |
| Finnish (not grpmax-eligible) | 0.00156% | 64,024 |

*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}

**HPD** population constraint: LOEUF 0.845, pLI 8.9816e-08, missense-Z 1.5213. *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):

- **hawkinsinuria** — Limited (AD)
- **tyrosinemia type III** — Definitive (AR)

## Protein context {#protein}

Residue **138** lies in the voc 1 domain.

AlphaFold model confidence (whole protein): pLDDT 96.00, 93% of residues very-high.

**4 experimental structure(s)** (PDB): [3ISQ](https://www.rcsb.org/structure/3ISQ), [5EC3](https://www.rcsb.org/structure/5EC3), [8IM2](https://www.rcsb.org/structure/8IM2), [8IM3](https://www.rcsb.org/structure/8IM3).

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

*Describes the biological roles of HPD (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:** HPD's established molecular role includes 4-hydroxyphenylpyruvate dioxygenase activity. p.Thr138= falls in the voc 1 domain.


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Tyrosine catabolism](https://reactome.org/content/detail/R-HSA-8963684) | curated |

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

**Molecular function:** 4-hydroxyphenylpyruvate dioxygenase activity, protein homodimerization activity.

**Biological process:** L-tyrosine catabolic process.

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-03.

**Submitter consensus:** conflicting (6 Benign, 1 Likely benign).

**Submission history:** 14 submissions (2015–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Fulgent Genetics, Fulgent Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2021-12-13 |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2015-03-03 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| Dr. Peter K. Rogan Lab, Western University |  | no classification provided | in vitro |  |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | criteria provided, single submitter | clinical testing | 2021-04-07 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-03 |

## Associated conditions {#conditions}

[hawkinsinuria](https://sugi.bio/atlas/disease/hawkinsinuria/), [tyrosinemia type III](https://sugi.bio/atlas/disease/tyrosinemia-type-iii/).

**Reported phenotype names (ClinVar):** Hawkinsinuria, Tyrosinemia type III, not provided, Clear cell carcinoma of kidney, not specified, Thyroid cancer, nonmedullary, 1, Cholangiocarcinoma, Hepatocellular carcinoma, Familial cancer of breast, none provided.

## Similar variants {#similar}

Related HPD variant pages (same residue, condition, or type): [HPD p.Thr138Met](/variant/hpd-p-thr138met), [HPD p.Thr138del](/variant/hpd-p-thr138del), [HPD p.Arg225Ter](/variant/hpd-p-arg225ter), [HPD p.Gln205Ter](/variant/hpd-p-gln205ter), [HPD p.Tyr160Cys](/variant/hpd-p-tyr160cys), [HPD p.Ala230Thr](/variant/hpd-p-ala230thr), [HPD p.Arg111Trp](/variant/hpd-p-arg111trp), [HPD p.Arg119Gln](/variant/hpd-p-arg119gln).

### 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 307485). 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.*