Is HAL p.Leu61= (c.181C>T) pathogenic?

HAL p.Leu61= (c.181C>T) is classified Uncertain significance in HAL (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-13). Ultra-rare (popmax 0.0657%, mid); Associated with histidinemia.

What condition is associated with HAL p.Leu61= (c.181C>T)?

HAL p.Leu61= (c.181C>T) is associated with histidinemia (ClinVar).

How common is HAL p.Leu61= (c.181C>T) in the general population?

HAL p.Leu61= (c.181C>T) is ultra-rare (popmax 0.0657%, mid) (gnomAD).

How is Histidinemia inherited?

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

HAL p.Leu61=

c.181C>T · rs139361462 · VCV883083

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0657%, mid)

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 2.8	GERP -0.17, phastCons 1
Overall
CADD	8.433	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0657% Middle Eastern · 4/6,084 alleles

Filtering AF 0.0224% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0135%

Overall 0.00613% 99/1,613,700 alleles · ultra-rare exomes 88/1,461,424 · genomes 11/152,276 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0657%	1,521
South Asian	0.0209%	4,795
Remaining individualsnot grpmax-eligible	0.0128%	7,810
European (non-Finnish)	0.00551%	18,154
African / African-American	0.00267%	37,482
Admixed American	0.00167%	60,018

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.Leu61=
Coding: c.181C>T
MANE Select: NM_002108
dbSNP: rs139361462
Type: single nucleotide variant
Location: chr12:95995730 (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-leu61 (accessed [today's date]).

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