Is EXT1 p.Pro489fs (c.1464_1465insAC) pathogenic?

EXT1 p.Pro489fs (c.14641465insAC) is classified Likely pathogenic in EXT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-22). No gnomAD frequency available for this variant; Associated with EXT1-related disorder.

What condition is associated with EXT1 p.Pro489fs (c.1464_1465insAC)?

EXT1 p.Pro489fs (c.1464_1465insAC) is associated with EXT1-related disorder (ClinVar).

How common is EXT1 p.Pro489fs (c.1464_1465insAC) in the general population?

EXT1 p.Pro489fs (c.1464_1465insAC) is no gnomAD frequency available for this variant (gnomAD).

EXT1 p.Pro489fs

c.1464_1465insAC · rs2488109170 · VCV2630816

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

EXT1-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 6 of 11
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 9.9	GERP 1.7, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: EXT1
Protein: p.Pro489fs
Coding: c.1464_1465insAC
MANE Select: NM_000127
dbSNP: rs2488109170
Type: Insertion
Location: chr8:117819747 (GRCh38)
Gene constraint: LOEUF 0.339 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 84.67 · 6 PDB

Full EXT1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

EXT1-related disorder

Similar variants

EXT1 p.Gly42fs Likely pathogenic ★ same condition
EXT1 p.Pro489Leu Uncertain significance ★ ⚠ same residue
EXT1 p.Pro489Thr Uncertain significance ★ ⚠ same residue
EXT1 p.Tyr629_Tyr630insPhe Uncertain significance ★ same condition
EXT1 p.Pro489= Likely benign ★ same residue
EXT1 p.Cys334Ter Pathogenic same condition
EXT1 c.1633-2A>G Pathogenic ★★ same condition
EXT1 c.1722+1G>A Pathogenic ★★ 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/ext1-p-pro489fs (accessed [today's date]).

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