Is EXT2 p.Arg23Gln (c.68G>A) pathogenic?

EXT2 p.Arg23Gln (c.68G>A) is classified Uncertain significance in EXT2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-24). AlphaMissense: likely benign (0.192); Ultra-rare (popmax 0.0121%, sas); Associated with Inborn genetic diseases.

What condition is associated with EXT2 p.Arg23Gln (c.68G>A)?

EXT2 p.Arg23Gln (c.68G>A) is associated with Inborn genetic diseases, exostoses, multiple, type 2 (ClinVar).

How common is EXT2 p.Arg23Gln (c.68G>A) in the general population?

EXT2 p.Arg23Gln (c.68G>A) is ultra-rare (popmax 0.0121%, sas) (gnomAD).

What do computational predictors say about EXT2 p.Arg23Gln (c.68G>A)?

AlphaMissense predicts likely benign (score 0.192) — an in-silico prediction, not a clinical call.

EXT2 p.Arg23Gln

c.68G>A · rs369368661 · VCV2550813

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.192 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0121%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.192	likely benign
REVEL	0.398	indeterminate
SaProt	LLR -1.78	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 12	GERP 2.3, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 99 kb · p 0.085 · regional, not allelic
Overall
CADD	24.9	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 0.0121% South Asian · 11/91,084 alleles

Filtering AF 0.00676% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00522%

Overall 0.00266% 43/1,614,002 alleles · ultra-rare exomes 40/1,461,888 · genomes 3/152,114 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0121%	8,280
Remaining individualsnot grpmax-eligible	0.008%	12,497
European (non-Finnish)	0.00229%	43,705

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.Arg23Gln
Coding: c.68G>A
MANE Select: NM_207122
dbSNP: rs369368661
Type: single nucleotide variant
Location: chr11:44107780 (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.Arg23Ter Pathogenic ★★ same residue
EXT2 p.Arg23= Likely benign ★ 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-arg23gln (accessed [today's date]).

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