Is HAL p.Glu472Lys (c.1414G>A) pathogenic?

HAL p.Glu472Lys (c.1414G>A) is classified Uncertain significance in HAL (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-06-08). AlphaMissense: likely pathogenic (0.9824); Very rare (popmax 0.00771%, nfe); Associated with histidinemia.

What condition is associated with HAL p.Glu472Lys (c.1414G>A)?

HAL p.Glu472Lys (c.1414G>A) is associated with histidinemia (ClinVar).

How common is HAL p.Glu472Lys (c.1414G>A) in the general population?

HAL p.Glu472Lys (c.1414G>A) is very rare (popmax 0.00771%, 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.Glu472Lys (c.1414G>A)?

AlphaMissense predicts likely pathogenic (score 0.9824) — an in-silico prediction, not a clinical call.

HAL p.Glu472Lys

c.1414G>A · rs147706824 · VCV310708

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9824 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00771%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

histidinemia

Computational evidence

Protein change
AlphaMissense	0.9824	likely pathogenic · top 8% in HAL
REVEL	0.867	moderately pathogenic-leaning
SaProt	LLR -11.18	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 7.6	GERP 1.6, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 22 kb · p 0.18 · regional, not allelic
Overall
CADD	28.2	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 0.00771% European (non-Finnish) · 91/1,179,850 alleles

Filtering AF 0.00639% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00592%

Overall 0.00632% 102/1,613,848 alleles · very rare exomes 96/1,461,684 · genomes 6/152,164 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00771%	12,965
African / African-American	0.00667%	14,984
Remaining individualsnot grpmax-eligible	0.0064%	15,619
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
East Asian	0.00223%	44,900

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.Glu472Lys
Coding: c.1414G>A
MANE Select: NM_002108
dbSNP: rs147706824
Type: single nucleotide variant
Location: chr12:95980661 (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.Glu472= 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.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-glu472lys (accessed [today's date]).

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