Is HAL p.Ser585Cys (c.1754C>G) pathogenic?

HAL p.Ser585Cys (c.1754C>G) is classified Uncertain significance in HAL (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-12). AlphaMissense: likely benign (0.1148); Rare (popmax 0.218%, sas); Associated with histidinemia.

What condition is associated with HAL p.Ser585Cys (c.1754C>G)?

HAL p.Ser585Cys (c.1754C>G) is associated with histidinemia (ClinVar).

How common is HAL p.Ser585Cys (c.1754C>G) in the general population?

HAL p.Ser585Cys (c.1754C>G) is rare (popmax 0.218%, sas) (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.Ser585Cys (c.1754C>G)?

AlphaMissense predicts likely benign (score 0.1148) — an in-silico prediction, not a clinical call.

HAL p.Ser585Cys

c.1754C>G · rs201632329 · VCV881408

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1148 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.218%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

histidinemia

Computational evidence

Protein change
AlphaMissense	0.1148	likely benign
REVEL	0.655	pathogenic-leaning
SaProt	LLR -11.73	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.7	GERP 1.6, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 22 kb · p 0.18 · regional, not allelic
Overall
CADD	26.4	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 0.218% South Asian · 198/90,926 alleles

Filtering AF 0.193% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.183%

Overall 0.0298% 478/1,605,654 alleles · rare exomes 452/1,453,330 · genomes 26/152,324 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.218%	459
Middle Eastern	0.0828%	1,208
Admixed American	0.03%	3,334
Remaining individualsnot grpmax-eligible	0.0257%	3,888
European (non-Finnish)	0.02%	4,988
African / African-American	0.00534%	18,721
Finnishnot grpmax-eligible	0.00312%	32,015

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.Ser585Cys
Coding: c.1754C>G
MANE Select: NM_002108
dbSNP: rs201632329
Type: single nucleotide variant
Location: chr12:95976607 (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-ser585cys (accessed [today's date]).

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