Is HAL p.Leu242Met (c.724C>A) pathogenic?

HAL p.Leu242Met (c.724C>A) is classified Uncertain significance in HAL (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-01-12). AlphaMissense: likely benign (0.2371); Rare (popmax 0.132%, mid); Associated with histidinemia.

What condition is associated with HAL p.Leu242Met (c.724C>A)?

HAL p.Leu242Met (c.724C>A) is associated with histidinemia (ClinVar).

How common is HAL p.Leu242Met (c.724C>A) in the general population?

HAL p.Leu242Met (c.724C>A) is rare (popmax 0.132%, mid) (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.Leu242Met (c.724C>A)?

AlphaMissense predicts likely benign (score 0.2371) — an in-silico prediction, not a clinical call.

HAL p.Leu242Met

c.724C>A · rs145831585 · VCV883800

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2371 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.132%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

histidinemia

Computational evidence

Protein change
AlphaMissense	0.2371	likely benign
REVEL	0.549	indeterminate
SaProt	LLR -9.56	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.8	GERP 1.6, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 22 kb · p 0.18 · regional, not allelic
Overall
CADD	24.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.132% Middle Eastern · 8/6,062 alleles

Filtering AF 0.0656% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0514%

Overall 0.031% 500/1,613,416 alleles · rare exomes 461/1,461,224 · genomes 39/152,192 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.351%	285
Middle Easterngrpmax	0.132%	758
South Asian	0.0703%	1,423
Remaining individualsnot grpmax-eligible	0.0608%	1,644
Admixed American	0.03%	3,333
European (non-Finnish)	0.0223%	4,485
East Asian	0.00446%	22,446
African / African-American	0.004%	24,976

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Leu242Met
Coding: c.724C>A
MANE Select: NM_002108
dbSNP: rs145831585
Type: single nucleotide variant
Location: chr12:95990524 (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.Phe485Leu Uncertain significance ★★ ⚠ same condition
HAL p.Thr123Met Uncertain significance ★★ ⚠ same condition
HAL c.1353+13A>G Benign ★★ 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-leu242met (accessed [today's date]).

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