Is EXT1 p.Pro120Gln (c.359C>A) pathogenic?

EXT1 p.Pro120Gln (c.359C>A) is classified Uncertain significance in EXT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-07). AlphaMissense: ambiguous (0.3474); Absent from gnomAD v4.1; Associated with chondrosarcoma.

What condition is associated with EXT1 p.Pro120Gln (c.359C>A)?

EXT1 p.Pro120Gln (c.359C>A) is associated with chondrosarcoma (ClinVar).

How common is EXT1 p.Pro120Gln (c.359C>A) in the general population?

EXT1 p.Pro120Gln (c.359C>A) is absent from gnomAD v4.1 (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.Pro120Gln (c.359C>A)?

AlphaMissense predicts ambiguous (score 0.3474) — an in-silico prediction, not a clinical call.

EXT1 p.Pro120Gln

c.359C>A · rs752226935 · VCV3241442

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3474 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

chondrosarcoma

Computational evidence

Protein change
AlphaMissense	0.3474	ambiguous
REVEL	0.903	moderately pathogenic-leaning
SaProt	LLR -10.21	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 5.8, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 371 bp · p 0.2 · regional, not allelic
Overall
CADD	33.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: EXT1
Protein: p.Pro120Gln
Coding: c.359C>A
MANE Select: NM_000127
dbSNP: rs752226935
Type: single nucleotide variant
Location: chr8:118110688 (GRCh38)
Gene constraint: LOEUF 0.339 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 84.67 · 6 PDB
Residue 120: an α-helix

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

For Chondrosarcoma (Orphanet):

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

Similar variants

EXT1 p.Pro120Leu Uncertain significance ★★ ⚠ same residue
EXT1 p.Arg340Cys Pathogenic/Likely pathogenic ★★ same condition
EXT1 p.Arg340Leu Pathogenic ★★ same condition
EXT1 p.Gln2Ter Pathogenic ★★ same condition
EXT1 p.Ala689Thr Uncertain significance ★★ ⚠ same condition
EXT1 p.Arg188Ser Uncertain significance ★★ ⚠ same condition
EXT1 p.Arg325Trp Uncertain significance ★★ ⚠ same condition
EXT1 p.Arg384Lys 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/ext1-p-pro120gln (accessed [today's date]).

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