Is HAL p.Pro259= (c.777A>G) pathogenic?

HAL p.Pro259= (c.777A>G) is classified Benign in HAL (ClinVar, Multiple submitters, 3 submitters; last evaluated 2018-01-12). Common (popmax 34.4%, eas) — too common for a highly-penetrant pathogenic allele; Associated with histidinemia.

What condition is associated with HAL p.Pro259= (c.777A>G)?

HAL p.Pro259= (c.777A>G) is associated with histidinemia (ClinVar).

How is Histidinemia inherited?

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

HAL p.Pro259=

Q: How common is HAL p.Pro259= (c.777A>G) in the general population?

HAL p.Pro259= (c.777A>G) is common (popmax 34.4%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.777A>G · rs36014288 · VCV310716

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Common

common (popmax 34.4%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

histidinemia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -13	GERP -3.1
Overall
CADD	0.242	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 34.4% East Asian · 15,409/44,826 alleles

Filtering AF 33.9% ClinGen BA1/BS1 input FAF95, joint · FAF99 33.7%

Overall 13.1% 210,987/1,610,892 alleles · common exomes 191,085/1,459,098 · genomes 19,902/151,794 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	34.4%	3
South Asian	22.9%	4
Finnishnot grpmax-eligible	18.2%	5
Remaining individualsnot grpmax-eligible	13.7%	7
Middle Eastern	12.6%	8
Amishnot grpmax-eligible	12%	8
African / African-American	11.8%	8
European (non-Finnish)	11.7%	9
Ashkenazi Jewishnot grpmax-eligible	8.71%	11
Admixed American	7.21%	14

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.Pro259=
Coding: c.777A>G
MANE Select: NM_002108
dbSNP: rs36014288
Type: single nucleotide variant
Location: chr12:95990471 (GRCh38)
Gene constraint: LOEUF 1.213 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.83
Residue 259: a UniProt-annotated variant site (in histid)

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 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
HAL p.Thr123Met 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-pro259 (accessed [today's date]).

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