Is HAL p.Arg369Gln (c.1106G>A) pathogenic?

HAL p.Arg369Gln (c.1106G>A) is classified Conflicting classifications of pathogenicity in HAL (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2024-06-01). AlphaMissense: ambiguous (0.3783); Rare (popmax 0.463%, nfe); Associated with histidinemia.

What condition is associated with HAL p.Arg369Gln (c.1106G>A)?

HAL p.Arg369Gln (c.1106G>A) is associated with histidinemia (ClinVar).

How common is HAL p.Arg369Gln (c.1106G>A) in the general population?

HAL p.Arg369Gln (c.1106G>A) is rare (popmax 0.463%, nfe) (gnomAD).

How is Histidinemia inherited?

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

What do computational predictors say about HAL p.Arg369Gln (c.1106G>A)?

AlphaMissense predicts ambiguous (score 0.3783) — an in-silico prediction, not a clinical call.

HAL p.Arg369Gln

c.1106G>A · rs117991621 · VCV310711

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

ambiguous

0.3783 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.463%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

histidinemia

Computational evidence

Protein change
AlphaMissense	0.3783	ambiguous
REVEL	0.823	moderately pathogenic-leaning
SaProt	LLR -7.65	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 1.6, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 22 kb · p 0.18 · regional, not allelic
Overall
CADD	29.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.463% European (non-Finnish) · 5,462/1,179,118 alleles

Filtering AF 0.453% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.449%

Overall 0.375% 6,053/1,613,096 alleles · rare exomes 5,647/1,460,940 · genomes 406/152,156 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.463%	216
Remaining individualsnot grpmax-eligible	0.375%	267
Ashkenazi Jewishnot grpmax-eligible	0.348%	287
Admixed American	0.197%	509
African / African-American	0.0921%	1,086
Finnishnot grpmax-eligible	0.0781%	1,280
Middle Eastern	0.066%	1,516
South Asian	0.0143%	7,005

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.Arg369Gln
Coding: c.1106G>A
MANE Select: NM_002108
dbSNP: rs117991621
Type: single nucleotide variant
Location: chr12:95986106 (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 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-arg369gln (accessed [today's date]).

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