Is EXT2 p.Pro247Ala (c.739C>G) pathogenic?

EXT2 p.Pro247Ala (c.739C>G) is classified Uncertain significance in EXT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-14). AlphaMissense: likely benign (0.0653); Absent from gnomAD v4.1; Associated with exostoses, multiple, type 2.

What condition is associated with EXT2 p.Pro247Ala (c.739C>G)?

EXT2 p.Pro247Ala (c.739C>G) is associated with exostoses, multiple, type 2 (ClinVar).

How common is EXT2 p.Pro247Ala (c.739C>G) in the general population?

EXT2 p.Pro247Ala (c.739C>G) is absent from gnomAD v4.1 (gnomAD).

How is Multiple osteochondromas inherited?

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

What do computational predictors say about EXT2 p.Pro247Ala (c.739C>G)?

AlphaMissense predicts likely benign (score 0.0653) — an in-silico prediction, not a clinical call.

EXT2 p.Pro247Ala

c.739C>G · rs1590555676 · VCV1950087

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0653 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

exostoses, multiple, type 2

Computational evidence

Protein change
AlphaMissense	0.0653	likely benign
REVEL	0.408	indeterminate
SaProt	LLR -5.82	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP -0.2, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 99 kb · p 0.085 · regional, not allelic
Overall
CADD	16.59	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

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: EXT2
Protein: p.Pro247Ala
Coding: c.739C>G
MANE Select: NM_207122
dbSNP: rs1590555676
Type: single nucleotide variant
Location: chr11:44114297 (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 p.Pro247Arg Uncertain significance ★★ ⚠ same residue
EXT2 p.Pro247Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
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

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-p-pro247ala (accessed [today's date]).

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