Is HAL p.Thr141= (c.423A>T) pathogenic?

HAL p.Thr141= (c.423A>T) is classified Benign in HAL (ClinVar, Multiple submitters, 3 submitters; last evaluated 2018-01-13). Common (popmax 31.9%, eas) — too common for a highly-penetrant pathogenic allele; Associated with histidinemia.

What condition is associated with HAL p.Thr141= (c.423A>T)?

HAL p.Thr141= (c.423A>T) is associated with histidinemia (ClinVar).

How is Histidinemia inherited?

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

HAL p.Thr141=

Q: How common is HAL p.Thr141= (c.423A>T) in the general population?

HAL p.Thr141= (c.423A>T) is common (popmax 31.9%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.423A>T · rs2302628 · VCV310721

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Common

common (popmax 31.9%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

histidinemia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.47	acceptor loss, 2 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP -0.29	GERP -3.1
Overall
CADD	3.307	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 31.9% East Asian · 14,313/44,826 alleles

Filtering AF 31.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 31.3%

Overall 7.62% 122,784/1,610,728 alleles · common exomes 110,363/1,458,474 · genomes 12,421/152,254 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	31.9%	3
South Asian	18.1%	6
Finnishnot grpmax-eligible	12.4%	8
Remaining individualsnot grpmax-eligible	8.44%	12
African / African-American	7.53%	13
Middle Eastern	6.23%	16
Ashkenazi Jewishnot grpmax-eligible	6.08%	16
European (non-Finnish)	5.83%	17
Admixed American	3.92%	26
Amishnot grpmax-eligible	1.75%	57

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.Thr141=
Coding: c.423A>T
MANE Select: NM_002108
dbSNP: rs2302628
Type: single nucleotide variant
Location: chr12:95993987 (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.Thr141Ala Uncertain significance ★ ⚠ same residue
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

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-thr141 (accessed [today's date]).

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