Is HAL p.Ile460Leu (c.1378A>C) pathogenic?

HAL p.Ile460Leu (c.1378A>C) is classified Benign in HAL (ClinVar, Multiple submitters, 2 submitters; last evaluated 2019-12-31). AlphaMissense: likely benign (0.1164); Low-frequency (popmax 1.81%, afr).

How common is HAL p.Ile460Leu (c.1378A>C) in the general population?

HAL p.Ile460Leu (c.1378A>C) is low-frequency (popmax 1.81%, afr) (gnomAD).

What do computational predictors say about HAL p.Ile460Leu (c.1378A>C)?

AlphaMissense predicts likely benign (score 0.1164) — an in-silico prediction, not a clinical call.

HAL p.Ile460Leu

c.1378A>C · rs142147961 · VCV776737

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1164 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.81%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1164	likely benign
REVEL	0.125	moderately benign-leaning
SaProt	LLR -5.81	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.22	GERP 0.65
Regional constraint	o/e 0.95	unconstrained · MANE · 22 kb · p 0.18 · regional, not allelic
Overall
CADD	11.94	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.81% African / African-American · 1,361/75,052 alleles

Filtering AF 1.73% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.7%

Overall 0.0948% 1,531/1,614,142 alleles · low-frequency exomes 718/1,461,794 · genomes 813/152,348 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.81%	55
Admixed American	0.123%	811
Middle Eastern	0.115%	866
Remaining individualsnot grpmax-eligible	0.107%	933
South Asian	0.00878%	11,385
European (non-Finnish)	0.00119%	84,283

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.Ile460Leu
Coding: c.1378A>C
MANE Select: NM_002108
dbSNP: rs142147961
Type: single nucleotide variant
Location: chr12:95980697 (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

Similar variants

HAL c.*392C>T Uncertain significance ★★ same type
HAL p.Arg9Cys Uncertain significance ★★ ⚠ same type
HAL p.Asn476Lys Uncertain significance ★★ ⚠ same type
HAL p.Glu472Lys Uncertain significance ★★ ⚠ same type
HAL p.Gly165Ser Uncertain significance ★★ ⚠ same type
HAL p.Ile458Thr Uncertain significance ★★ ⚠ same type
HAL p.Leu242Met Uncertain significance ★★ ⚠ same type
HAL p.Phe485Leu Uncertain significance ★★ ⚠ same type

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-ile460leu (accessed [today's date]).

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