Is HAL p.Thr426Arg (c.1277C>G) pathogenic?

HAL p.Thr426Arg (c.1277C>G) is classified Uncertain significance in HAL (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-12). AlphaMissense: likely pathogenic (0.9708); Very rare (popmax 0.000638%, nfe); Associated with histidinemia.

What condition is associated with HAL p.Thr426Arg (c.1277C>G)?

HAL p.Thr426Arg (c.1277C>G) is associated with histidinemia (ClinVar).

How common is HAL p.Thr426Arg (c.1277C>G) in the general population?

HAL p.Thr426Arg (c.1277C>G) is very rare (popmax 0.000638%, 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.Thr426Arg (c.1277C>G)?

AlphaMissense predicts likely pathogenic (score 0.9708) — an in-silico prediction, not a clinical call.

HAL p.Thr426Arg

c.1277C>G · rs1565988698 · VCV883014

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9708 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000638%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

histidinemia

Computational evidence

Protein change
AlphaMissense	0.9708	likely pathogenic
REVEL	0.883	moderately pathogenic-leaning
SaProt	LLR -15.76	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.4, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 22 kb · p 0.18 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000638% European (non-Finnish) · 7/1,096,974 alleles

Filtering AF 0.000265% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000171%

Overall 0.00046% 7/1,521,954 alleles · very rare exomes 7/1,369,628 · genomes 0/152,326 · joint denominator

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.Thr426Arg
Coding: c.1277C>G
MANE Select: NM_002108
dbSNP: rs1565988698
Type: single nucleotide variant
Location: chr12:95983921 (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-thr426arg (accessed [today's date]).

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