# NM_002150.3(HPD):c.294C>T (p.Phe98=)

https://sugi.bio/variant/hpd-p-phe98

## Summary

**HPD p.Phe98= (c.294C>T)** is classified **Conflicting classifications of pathogenicity** in HPD (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-05-01). Rare (popmax 0.125%, amr); Associated with hawkinsinuria.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs117079110 · 3 submitters · 2 linked conditions · rare (popmax 0.125%, amr)

> **Built without this gene's context.** ClinVar files this variant under an overlapping gene, so its own gene's record set does not contain it and this page is assembled from the variant alone. Gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up — absent from this page, not from the data.

## For patients & families {#patients}

This is a change in the HPD gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 3 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) |

**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.Phe98= |
| Coding change (HGVS c.) | c.294C>T |
| MANE Select transcript | [NM_002150](https://www.ncbi.nlm.nih.gov/nuccore/NM_002150) |
| dbSNP | [rs117079110](https://www.ncbi.nlm.nih.gov/snp/rs117079110/) |
| Variant type | single nucleotide variant |
| Location | chr12:121856354-121856354 (GRCh38) |
| ClinVar | [VCV307487](https://www.ncbi.nlm.nih.gov/clinvar/variation/307487/) |

**All HGVS expressions:** `NC_000012.11:g.122294260G>A`, `NC_000012.12:g.121856354G>A`, `NG_016461.1:g.37258C>T`, `NM_001171993.2:c.177C>T`, `NM_002150.3:c.294C>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 -2.999, GERP -3.81 — fast-evolving / accelerated position
- CADD: **PHRED 3.102**. 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 looked up on this page** — it was served without the gene's SpliceAI index, so no lookup was made. This is a gap in this page, not in the data, and says nothing about whether a splicing effect is predicted.
- Population frequency (gnomAD v4.1): grpmax **0.125%** (amr) · FAF95 0.102% · FAF99 0.0938% · 75/59,996 in the highest group · 1,170/1,614,054 alleles overall — rare (popmax 0.125%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.125% | 800 |
| European (non-Finnish) | 0.0871% | 1,148 |
| Remaining individuals (not grpmax-eligible) | 0.0672% | 1,488 |
| African / African-American | 0.024% | 4,167 |
| Finnish (not grpmax-eligible) | 0.00625% | 16,008 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00338% | 29,606 |
| East Asian | 0.00223% | 44,882 |
| South Asian | 0.0011% | 91,082 |

*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.*

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-05-01.

**Submitter consensus:** conflicting (2 Benign, 1 Uncertain significance, 1 Likely benign).

**Submission history:** 4 submissions (2018–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2025-12-26 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2026-05-01 |

## 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, 4-HYDROXYPHENYLPYRUVIC ACID OXIDASE DEFICIENCY, Tyrosinemia type 3, 4-alpha hydroxyphenylpyruvic acid oxidase deficiency, 4-alpha hydroxyphenylpyruvate dioxygenase deficiency, 4-Hydroxyphenylpyruvate dioxygenase deficiency, none provided.

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 307487). 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.*