Is EXT2 c.1663-1G>A pathogenic?

EXT2 c.1663-1G>A is classified Likely pathogenic in EXT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-09). Very rare (popmax 0.00223%, eas); Associated with exostoses, multiple, type 2.

What condition is associated with EXT2 c.1663-1G>A?

EXT2 c.1663-1G>A is associated with exostoses, multiple, type 2 (ClinVar).

How common is EXT2 c.1663-1G>A in the general population?

EXT2 c.1663-1G>A is very rare (popmax 0.00223%, eas) (gnomAD).

How is Multiple osteochondromas inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

EXT2 c.1663-1G>A

rs1194348744 · VCV1925953

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

canonical splice-site (±1/±2)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

exostoses, multiple, type 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	canonical splice-site (±1/±2)	predicted loss-of-function in a haploinsufficient gene (ClinGen)
Splicing
Splice region	acceptor -1	canonical splice dinucleotide (acceptor -1) · inside the BP7-excluded zone
SpliceAI	Δ1.00	acceptor loss, 1 bp away · masked 0 · deltas
Pangolin	Δ0.87	loss · gain 0.79 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 12	GERP -2.6, phastCons 1
Non-coding constraint	Z 2.10	1 kb window · o/e 0.85 · regional · uncalibrated
Overall
CADD	36.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,888 alleles

Overall 6.2e-05% 1/1,613,686 alleles · very rare exomes 0/1,461,592 · genomes 1/152,094 · 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: EXT2
Coding: c.1663-1G>A
MANE Select: NM_207122
dbSNP: rs1194348744
Type: single nucleotide variant
Location: chr11:44232352 (GRCh38)
Gene constraint: LOEUF 0.775 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 87.59 · 6 PDB

Full EXT2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

exostoses, multiple, type 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Multiple osteochondromas (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood
Prevalence: >1 / 1000 (Specific population)

Similar variants

EXT2 c.1079+1G>A Pathogenic ★★ same condition
EXT2 c.1079+1G>T Pathogenic ★★ same condition
EXT2 c.1173+1G>A Pathogenic ★★ same condition
EXT2 c.1662+1G>C Likely pathogenic ★★ same condition
EXT2 c.536+1G>A Pathogenic ★★ same condition
EXT2 c.626+1G>A Pathogenic ★★ same condition
EXT2 c.626+1G>C Pathogenic ★★ same condition
EXT2 c.626+1G>T Pathogenic/Likely 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/ext2-c-1663-minus-1g-a (accessed [today's date]).

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