Is ASL p.Ile28Thr (c.83T>C) pathogenic?

ASL p.Ile28Thr (c.83T>C) is classified Uncertain significance in ASL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-30). AlphaMissense: likely pathogenic (0.6115); Very rare (popmax 0.000424%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ASL p.Ile28Thr (c.83T>C)?

ASL p.Ile28Thr (c.83T>C) is associated with Inborn genetic diseases (ClinVar).

How common is ASL p.Ile28Thr (c.83T>C) in the general population?

ASL p.Ile28Thr (c.83T>C) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about ASL p.Ile28Thr (c.83T>C)?

AlphaMissense predicts likely pathogenic (score 0.6115) — an in-silico prediction, not a clinical call.

ASL p.Ile28Thr

c.83T>C · rs1786513250 · VCV2598643

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6115 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6115	likely pathogenic
REVEL	0.864	moderately pathogenic-leaning
SaProt	LLR -10.15	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 7.9	GERP 1.5, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 17 kb · p 0.00078 · regional, not allelic
Overall
CADD	23.6	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 0.000424% European (non-Finnish) · 5/1,180,024 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000342% 5/1,461,790 alleles · very rare

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: ASL
Protein: p.Ile28Thr
Coding: c.83T>C
MANE Select: NM_000048
dbSNP: rs1786513250
Type: single nucleotide variant
Location: chr7:66081873 (GRCh38)
Gene constraint: LOEUF 0.937 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 96.51 · 2 PDB
Residue 28: an α-helix

Full ASL gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ASL p.Arg186Gln Pathogenic ★★ ⚠ same condition
ASL p.Ala26Thr Uncertain significance ★★ ⚠ same condition
ASL p.Ala2Asp Uncertain significance ★★ ⚠ same condition
ASL p.Arg151His Uncertain significance ★★ ⚠ same condition
ASL p.Arg32Trp Uncertain significance ★★ ⚠ same condition
ASL p.Val196Ile Uncertain significance ★★ ⚠ same condition
ASL c.348+5T>C Uncertain significance ★ same condition
ASL p.Arg141Lys 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/asl-p-ile28thr (accessed [today's date]).

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