# NM_002108.4(HAL):c.623G>A (p.Arg208Gln)

https://sugi.bio/variant/hal-p-arg208gln

## Summary

**HAL p.Arg208Gln (c.623G>A)** is classified **Uncertain significance** in HAL (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-13). AlphaMissense: ambiguous (0.4227); Very rare (popmax 0.00534%, afr); Associated with histidinemia.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs121434328 · 1 submitter · 1 linked condition · AlphaMissense ambiguous · very rare (popmax 0.00534%, afr)

## For patients & families {#patients}

This is a change in the HAL gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, 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.Arg208Gln |
| Coding change (HGVS c.) | c.623G>A |
| MANE Select transcript | [NM_002108](https://www.ncbi.nlm.nih.gov/nuccore/NM_002108) |
| dbSNP | [rs121434328](https://www.ncbi.nlm.nih.gov/snp/rs121434328/) |
| Variant type | single nucleotide variant |
| Location | chr12:95992772-95992772 (GRCh38) |
| ClinVar | [VCV881468](https://www.ncbi.nlm.nih.gov/clinvar/variation/881468/) |

**All HGVS expressions:** `NC_000012.11:g.96386550C>T`, `NC_000012.12:g.95992772C>T`, `NG_008180.1:g.8522G>A`, `NM_001258333.2:c.-2G>A`, `NM_001258334.2:c.623G>A`, `NM_002108.4:c.623G>A`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense makes no call; REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate — descriptive only.

- AlphaMissense **ambiguous** (0.4227) — no call either way
- REVEL 0.929 (moderately pathogenic-leaning)
- SaProt LLR -8.882 (tolerated)
- → **In-silico consensus:** REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate
- SpliceAI predicts **acceptor loss** (Δ 0.32) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 7.609, GERP 1.25, phastCons 1 — highly conserved
- CADD: **PHRED 29.9**. 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 0.95** across the covering region of the MANE Select transcript (95,974,235–95,995,910), spanning 21,675 bp. Chi-square p 0.18. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.32**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**. Largest is acceptor loss.
- SpliceAI deltas (masked): acceptor loss **0.32**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
- Pangolin: Δ**0.31** (loss), gain 0.00 / loss 0.31. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00534%** (afr) · FAF95 0.00175% · FAF99 0.00104% · 4/74,876 in the highest group · 30/1,612,620 alleles overall — very rare (popmax 0.00534%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00534% | 18,719 |
| Remaining individuals (not grpmax-eligible) | 0.0048% | 20,815 |
| East Asian | 0.00446% | 22,436 |
| European (non-Finnish) | 0.00178% | 56,133 |

*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}

Residue **208** lies in a UniProt-annotated variant site (in histid).

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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2018-01-13.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-13 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Histidinemia, Deficiency of histidine ammonia-lyase, Hyperhistidinemia, HAL DEFICIENCY, HIS DEFICIENCY, HISTIDASE DEFICIENCY, HISTIDINE AMMONIA-LYASE DEFICIENCY.

## Similar variants {#similar}

Related HAL variant pages (same residue, condition, or type): [HAL p.Arg208Trp](/variant/hal-p-arg208trp), [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).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 881468). 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.*