# NM_002108.4(HAL):c.827C>T (p.Pro276Leu)

https://sugi.bio/variant/hal-p-pro276leu

## Summary

**HAL p.Pro276Leu (c.827C>T)** is classified **Uncertain significance** in HAL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-16). AlphaMissense: ambiguous (0.4559); Very rare (popmax 0.00127%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense ambiguous · very rare (popmax 0.00127%, nfe)

## 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.

*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.*

**Support & next steps:** [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.Pro276Leu |
| Coding change (HGVS c.) | c.827C>T |
| MANE Select transcript | [NM_002108](https://www.ncbi.nlm.nih.gov/nuccore/NM_002108) |
| Variant type | single nucleotide variant |
| Location | chr12:95990421-95990421 (GRCh38) |
| ClinVar | [VCV4831769](https://www.ncbi.nlm.nih.gov/clinvar/variation/4831769/) |

**All HGVS expressions:** `NC_000012.11:g.96384199G>A`, `NC_000012.12:g.95990421G>A`, `NG_008180.1:g.10873C>T`, `NM_001258333.2:c.203C>T`, `NM_001258334.2:c.827C>T`, `NM_002108.4:c.827C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **ambiguous** (0.4559) — no call either way
- REVEL 0.742 (pathogenic-leaning)
- SaProt LLR -9.592 (tolerated)
- → **In-silico consensus:** REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate
- SpliceAI predicts **donor loss** (Δ 0.20) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 11.482, GERP 1.55, phastCons 1 — highly conserved
- CADD: **PHRED 34.0**. 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 **0.00**, donor loss **0.20**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss, 28 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **0.00127%** (nfe) · FAF95 0.000764% · FAF99 0.000606% · 15/1,179,402 in the highest group · 16/1,613,348 alleles overall — very rare (popmax 0.00127%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,468 |
| European (non-Finnish) (grpmax) | 0.00127% | 78,627 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-12-16.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-12-16 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related HAL variant pages (same residue, condition, or type): [HAL p.Pro276Ser](/variant/hal-p-pro276ser), [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.Ile458Thr](/variant/hal-p-ile458thr), [HAL p.Leu242Met](/variant/hal-p-leu242met).

### 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 4831769). 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.*