Is HAL p.Ile458Thr (c.1373T>C) pathogenic?

HAL p.Ile458Thr (c.1373T>C) is classified Uncertain significance in HAL (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-02-18). AlphaMissense: likely benign (0.3101); Ultra-rare (popmax 0.0152%, nfe).

How common is HAL p.Ile458Thr (c.1373T>C) in the general population?

HAL p.Ile458Thr (c.1373T>C) is ultra-rare (popmax 0.0152%, nfe) (gnomAD).

What do computational predictors say about HAL p.Ile458Thr (c.1373T>C)?

AlphaMissense predicts likely benign (score 0.3101) — an in-silico prediction, not a clinical call.

HAL p.Ile458Thr

c.1373T>C · rs377299266 · VCV2384474

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3101 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0152%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3101	likely benign
REVEL	0.896	moderately pathogenic-leaning
SaProt	LLR -11.14	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.6, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 22 kb · p 0.18 · regional, not allelic
Overall
CADD	26.4	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 0.0152% European (non-Finnish) · 179/1,179,888 alleles

Filtering AF 0.0133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0126%

Overall 0.0113% 183/1,613,940 alleles · ultra-rare exomes 178/1,461,714 · genomes 5/152,226 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0152%	6,592
Remaining individualsnot grpmax-eligible	0.0048%	20,827
South Asian	0.0011%	91,084

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.Ile458Thr
Coding: c.1373T>C
MANE Select: NM_002108
dbSNP: rs377299266
Type: single nucleotide variant
Location: chr12:95980702 (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.Leu242Met Uncertain significance ★★ ⚠ same type
HAL p.Phe485Leu Uncertain significance ★★ ⚠ same type
HAL p.Thr123Met 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-ile458thr (accessed [today's date]).

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