Is EXT2 p.Pro243Arg (c.728C>G) pathogenic?

EXT2 p.Pro243Arg (c.728C>G) is classified Likely benign in EXT2 (ClinVar, Single submitter, 2 submitters; last evaluated 2026-01-04). AlphaMissense: likely benign (0.0924); Ultra-rare (popmax 0.0168%, nfe); Associated with exostoses, multiple, type 2.

What condition is associated with EXT2 p.Pro243Arg (c.728C>G)?

EXT2 p.Pro243Arg (c.728C>G) is associated with exostoses, multiple, type 2 (ClinVar).

How common is EXT2 p.Pro243Arg (c.728C>G) in the general population?

EXT2 p.Pro243Arg (c.728C>G) is ultra-rare (popmax 0.0168%, nfe) (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.Pro243Arg (c.728C>G)?

AlphaMissense predicts likely benign (score 0.0924) — an in-silico prediction, not a clinical call.

EXT2 p.Pro243Arg

c.728C>G · rs200032672 · VCV1014547

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0924 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0168%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

exostoses, multiple, type 2

Computational evidence

Protein change
AlphaMissense	0.0924	likely benign
REVEL	0.603	indeterminate
SaProt	LLR -9.26	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 2.2	GERP 2.6, phastCons 0.98
Regional constraint	o/e 0.93	unconstrained · MANE · 99 kb · p 0.085 · regional, not allelic
Overall
CADD	21.4	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

Grpmax group 0.0168% European (non-Finnish) · 198/1,179,678 alleles

Filtering AF 0.0149% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0141%

Overall 0.0126% 203/1,613,596 alleles · ultra-rare exomes 196/1,461,458 · genomes 7/152,138 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0168%	5,958
Remaining individualsnot grpmax-eligible	0.0048%	20,823
Admixed American	0.00167%	59,984
African / African-American	0.00134%	74,880

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
Protein: p.Pro243Arg
Coding: c.728C>G
MANE Select: NM_207122
dbSNP: rs200032672
Type: single nucleotide variant
Location: chr11:44114286 (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.Pro243fs Pathogenic 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
EXT2 c.626+1G>C 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-pro243arg (accessed [today's date]).

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