Is EXT2 p.Pro247Arg (c.740C>G) pathogenic?

EXT2 p.Pro247Arg (c.740C>G) is classified Uncertain significance in EXT2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-28). AlphaMissense: likely benign (0.0911); Ultra-rare (popmax 0.02%, amr); Associated with Inborn genetic diseases.

What condition is associated with EXT2 p.Pro247Arg (c.740C>G)?

EXT2 p.Pro247Arg (c.740C>G) is associated with Inborn genetic diseases, exostoses, multiple, type 2 (ClinVar).

How common is EXT2 p.Pro247Arg (c.740C>G) in the general population?

EXT2 p.Pro247Arg (c.740C>G) is ultra-rare (popmax 0.02%, amr) (gnomAD).

What do computational predictors say about EXT2 p.Pro247Arg (c.740C>G)?

AlphaMissense predicts likely benign (score 0.0911) — an in-silico prediction, not a clinical call.

EXT2 p.Pro247Arg

c.740C>G · rs372237191 · VCV1040250

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0911 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.02%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0911	likely benign
REVEL	0.542	indeterminate
SaProt	LLR -9.14	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 0.78, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 99 kb · p 0.085 · regional, not allelic
Overall
CADD	22.0	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

Grpmax group 0.02% Admixed American · 12/59,980 alleles

Filtering AF 0.0115% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00898%

Overall 0.000744% 12/1,612,490 alleles · ultra-rare exomes 11/1,460,364 · genomes 1/152,126 · 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
Protein: p.Pro247Arg
Coding: c.740C>G
MANE Select: NM_207122
dbSNP: rs372237191
Type: single nucleotide variant
Location: chr11:44114298 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: exostoses, multiple, type 2

Similar variants

EXT2 p.Pro247Ala 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-pro247arg (accessed [today's date]).

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