Is HAL p.Arg9Cys (c.25C>T) pathogenic?

HAL p.Arg9Cys (c.25C>T) is classified Uncertain significance in HAL (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-11-03). AlphaMissense: likely pathogenic (0.6443); Ultra-rare (popmax 0.0509%, nfe); Associated with histidinemia.

What condition is associated with HAL p.Arg9Cys (c.25C>T)?

HAL p.Arg9Cys (c.25C>T) is associated with histidinemia (ClinVar).

How common is HAL p.Arg9Cys (c.25C>T) in the general population?

HAL p.Arg9Cys (c.25C>T) is ultra-rare (popmax 0.0509%, 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.Arg9Cys (c.25C>T)?

AlphaMissense predicts likely pathogenic (score 0.6443) — an in-silico prediction, not a clinical call.

HAL p.Arg9Cys

c.25C>T · rs201646460 · VCV883086

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6443 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0509%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

histidinemia

Computational evidence

Protein change
AlphaMissense	0.6443	likely pathogenic
REVEL	0.678	pathogenic-leaning
SaProt	LLR -8.31	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 22 kb · p 0.18 · regional, not allelic
Overall
CADD	32.0	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 0.0509% European (non-Finnish) · 600/1,179,904 alleles

Filtering AF 0.0475% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0461%

Overall 0.0386% 620/1,605,864 alleles · ultra-rare exomes 583/1,453,660 · genomes 37/152,204 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0509%	1,967
Remaining individualsnot grpmax-eligible	0.016%	6,242
African / African-American	0.0107%	9,367
Finnishnot grpmax-eligible	0.00178%	56,040
Admixed American	0.00167%	60,008

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.Arg9Cys
Coding: c.25C>T
MANE Select: NM_002108
dbSNP: rs201646460
Type: single nucleotide variant
Location: chr12:95995886 (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.Arg9His Uncertain significance ★ ⚠ same residue
HAL c.*392C>T 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-arg9cys (accessed [today's date]).

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