Is HAL p.Pro598= (c.1794G>A) pathogenic?

HAL p.Pro598= (c.1794G>A) is classified Uncertain significance in HAL (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-13). Ultra-rare (popmax 0.0178%, eas); Associated with histidinemia.

What condition is associated with HAL p.Pro598= (c.1794G>A)?

HAL p.Pro598= (c.1794G>A) is associated with histidinemia (ClinVar).

How common is HAL p.Pro598= (c.1794G>A) in the general population?

HAL p.Pro598= (c.1794G>A) is ultra-rare (popmax 0.0178%, eas) (gnomAD).

How is Histidinemia inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

HAL p.Pro598=

c.1794G>A · rs149461774 · VCV883750

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0178%, eas)

Conditions

histidinemia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.101	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -7.4	GERP -3.1
Overall
CADD	2.001	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0178% East Asian · 8/44,886 alleles

Filtering AF 0.00901% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00842%

Overall 0.00892% 144/1,614,108 alleles · ultra-rare exomes 123/1,461,810 · genomes 21/152,298 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	0.219%	456
East Asiangrpmax	0.0178%	5,611
European (non-Finnish)	0.0105%	9,516
Admixed American	0.00666%	15,006
Remaining individualsnot grpmax-eligible	0.0048%	20,836
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,604
African / African-American	0.00133%	75,034
South Asian	0.0011%	91,076

Amish shows a higher raw frequency than the grpmax group above it. 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.

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: HAL
Protein: p.Pro598=
Coding: c.1794G>A
MANE Select: NM_002108
dbSNP: rs149461774
Type: single nucleotide variant
Location: chr12:95976468 (GRCh38)
Gene constraint: LOEUF 1.213 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.83

Full HAL gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

histidinemia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Histidinemia (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Sweden)

Similar variants

HAL p.Pro598Leu Uncertain significance ★ ⚠ same residue
HAL c.*392C>T Uncertain significance ★★ same condition
HAL p.Arg9Cys Uncertain significance ★★ ⚠ same condition
HAL p.Asn476Lys Uncertain significance ★★ ⚠ same condition
HAL p.Glu472Lys Uncertain significance ★★ ⚠ same condition
HAL p.Gly165Ser Uncertain significance ★★ ⚠ same condition
HAL p.Leu242Met Uncertain significance ★★ ⚠ same condition
HAL p.Phe485Leu Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/hal-p-pro598 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown