# NM_002108.4(HAL):c.492C>T (p.Tyr164=)

https://sugi.bio/variant/hal-p-tyr164

## Summary

**HAL p.Tyr164= (c.492C>T)** is classified **Benign/Likely benign** in HAL (ClinVar, Multiple submitters, 3 submitters; last evaluated 2019-01-08). Low-frequency (popmax 3.62%, afr); Associated with histidinemia.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs17024973 · 3 submitters · 1 linked condition · low-frequency (popmax 3.62%, afr)

## For patients & families {#patients}

This is a change in the HAL gene that is classified as benign/likely benign — not considered disease-causing, submitted by 3 submitters, and is linked to histidinemia.

*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 / 100 000 (Sweden) |

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

- Histidinuria — Obligate (100%)
- Hyperhistidinemia — Obligate (100%)
- Atypical behavior — Very rare (<4-1%)
- Hyperactivity — Very rare (<4-1%)
- Specific learning disability — Very rare (<4-1%)
- Abnormality of speech or vocalization — Very rare (<4-1%)
- Moderate global developmental delay — Very rare (<4-1%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0006661/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [HAL](https://sugi.bio/atlas/gene/HAL/) |
| Protein change (HGVS p.) | p.Tyr164= |
| Coding change (HGVS c.) | c.492C>T |
| MANE Select transcript | [NM_002108](https://www.ncbi.nlm.nih.gov/nuccore/NM_002108) |
| dbSNP | [rs17024973](https://www.ncbi.nlm.nih.gov/snp/rs17024973/) |
| Variant type | single nucleotide variant |
| Location | chr12:95993831-95993831 (GRCh38) |
| ClinVar | [VCV773028](https://www.ncbi.nlm.nih.gov/clinvar/variation/773028/) |

**All HGVS expressions:** `NC_000012.11:g.96387609G>A`, `NC_000012.12:g.95993831G>A`, `NG_008180.1:g.7463C>T`, `NM_001258333.2:c.-74+95C>T`, `NM_001258334.2:c.492C>T`, `NM_002108.4:c.492C>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 -6.926, GERP -3.13 — fast-evolving / accelerated position
- CADD: **PHRED 8.294**. 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: **below the reporting threshold**. This position is scored for a different substitution (G>C, Δ0.32 acceptor loss), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **3.62%** (afr) · FAF95 3.51% · FAF99 3.46% · 2,676/73,880 in the highest group · 2,973/1,563,514 alleles overall — low-frequency (popmax 3.62%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 3.62% | 28 |
| Remaining individuals (not grpmax-eligible) | 0.179% | 557 |
| Admixed American | 0.17% | 588 |
| Middle Eastern | 0.0503% | 1,989 |
| South Asian | 0.00889% | 11,253 |
| European (non-Finnish) | 0.00644% | 15,535 |
| East Asian | 0.00224% | 44,650 |
| Finnish (not grpmax-eligible) | 0.00156% | 63,974 |

*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}

**HAL** population constraint: LOEUF 1.213, pLI 2.8209e-18, missense-Z 0.49342. *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):

- **histidinemia** — Limited (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 90.83, 75% of residues very-high.

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

*Describes the biological roles of HAL (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:** HAL's established molecular role includes histidine ammonia-lyase activity.


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Histidine catabolism](https://reactome.org/content/detail/R-HSA-70921) | curated |

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

**Molecular function:** histidine ammonia-lyase activity.

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2019-01-08.

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

**Submission history:** 3 submissions (2017–2019); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2019-01-08 |
| Illumina Laboratory Services, Illumina | Likely benign | criteria provided, single submitter | clinical testing | 2017-04-27 |
| Breakthrough Genomics, Breakthrough Genomics | Likely benign | criteria provided, single submitter | not provided |  |

## Associated conditions {#conditions}

[histidinemia](https://sugi.bio/atlas/disease/histidinemia/).

**Reported phenotype names (ClinVar):** Histidinemia, not provided, none provided, Hyperhistidinemia, Deficiency of histidine ammonia-lyase, HAL DEFICIENCY, HIS DEFICIENCY, HISTIDASE DEFICIENCY, HISTIDINE AMMONIA-LYASE DEFICIENCY.

## Similar variants {#similar}

Related HAL variant pages (same residue, condition, or type): [HAL c.*392C>T](/variant/hal-c-star-392c-t), [HAL p.Arg9Cys](/variant/hal-p-arg9cys), [HAL p.Asn476Lys](/variant/hal-p-asn476lys), [HAL p.Glu472Lys](/variant/hal-p-glu472lys), [HAL p.Gly165Ser](/variant/hal-p-gly165ser), [HAL p.Leu242Met](/variant/hal-p-leu242met), [HAL p.Phe485Leu](/variant/hal-p-phe485leu), [HAL p.Thr123Met](/variant/hal-p-thr123met).

### 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 773028). 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.*