Is EXT1 p.Pro489Leu (c.1466C>T) pathogenic?

EXT1 p.Pro489Leu (c.1466C>T) is classified Uncertain significance in EXT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-14). AlphaMissense: likely pathogenic (0.7835); Very rare (popmax 0.000169%, nfe); Associated with chondrosarcoma.

What condition is associated with EXT1 p.Pro489Leu (c.1466C>T)?

EXT1 p.Pro489Leu (c.1466C>T) is associated with chondrosarcoma, exostoses, multiple, type 1 (ClinVar).

How common is EXT1 p.Pro489Leu (c.1466C>T) in the general population?

EXT1 p.Pro489Leu (c.1466C>T) is very rare (popmax 0.000169%, nfe) (gnomAD).

How is Chondrosarcoma inherited?

Typically Not applicable, Unknown (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about EXT1 p.Pro489Leu (c.1466C>T)?

AlphaMissense predicts likely pathogenic (score 0.7835) — an in-silico prediction, not a clinical call.

EXT1 p.Pro489Leu

c.1466C>T · VCV3595043

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7835 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

chondrosarcoma

Computational evidence

Protein change
AlphaMissense	0.7835	likely pathogenic
REVEL	0.861	moderately pathogenic-leaning
SaProt	LLR -13.13	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 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 17 kb · p 0.25 · regional, not allelic
Overall
CADD	29.3	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 0.000169% European (non-Finnish) · 2/1,180,034 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,613,452 alleles · very rare exomes 2/1,461,134 · genomes 0/152,318 · joint denominator

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: EXT1
Protein: p.Pro489Leu
Coding: c.1466C>T
MANE Select: NM_000127
Type: single nucleotide variant
Location: chr8:117819746 (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

chondrosarcoma — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: exostoses, multiple, type 1

For Chondrosarcoma (Orphanet):

Inheritance: Not applicable, Unknown
Onset: Adult
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

EXT1 p.Pro489Thr Uncertain significance ★ ⚠ same residue
EXT1 p.Pro489= Likely benign ★ same residue
EXT1 c.1418-1G>A Pathogenic ★★ same condition
EXT1 c.1418-2A>G Pathogenic ★★ same condition
EXT1 c.1536+1G>A Pathogenic ★★ same condition
EXT1 c.1723-2A>T Pathogenic/Likely pathogenic ★★ same condition
EXT1 c.1884-1G>C Pathogenic ★★ same condition
EXT1 c.962+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-pro489leu (accessed [today's date]).

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