Is HAL p.Pro575Leu (c.1724C>T) pathogenic?

HAL p.Pro575Leu (c.1724C>T) is classified Uncertain significance in HAL (ClinVar, Single submitter, 1 submitter; last evaluated 2017-11-20). AlphaMissense: likely pathogenic (0.7203); Rare (popmax 0.165%, eas); Associated with histidinemia.

What condition is associated with HAL p.Pro575Leu (c.1724C>T)?

HAL p.Pro575Leu (c.1724C>T) is associated with histidinemia (ClinVar).

How common is HAL p.Pro575Leu (c.1724C>T) in the general population?

HAL p.Pro575Leu (c.1724C>T) is rare (popmax 0.165%, eas) (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.Pro575Leu (c.1724C>T)?

AlphaMissense predicts likely pathogenic (score 0.7203) — an in-silico prediction, not a clinical call.

HAL p.Pro575Leu

c.1724C>T · rs141674733 · VCV881409

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7203 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.165%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

histidinemia

Computational evidence

Protein change
AlphaMissense	0.7203	likely pathogenic
REVEL	0.548	indeterminate
SaProt	LLR -9.40	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.6, 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 0.165% East Asian · 74/44,884 alleles

Filtering AF 0.135% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.124%

Overall 0.052% 839/1,612,728 alleles · rare exomes 789/1,460,394 · genomes 50/152,334 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.165%	607
European (non-Finnish)	0.0618%	1,619
Remaining individualsnot grpmax-eligible	0.0352%	2,839
African / African-American	0.012%	8,336
Admixed American	0.00666%	15,008
Finnishnot grpmax-eligible	0.00156%	64,040
South Asian	0.0011%	91,064

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.Pro575Leu
Coding: c.1724C>T
MANE Select: NM_002108
dbSNP: rs141674733
Type: single nucleotide variant
Location: chr12:95976637 (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-pro575leu (accessed [today's date]).

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