Is EXT2 p.Arg299His (c.896G>A) pathogenic?

EXT2 p.Arg299His (c.896G>A) is classified Benign/Likely benign in EXT2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-18). AlphaMissense: ambiguous (0.3585); Rare (popmax 0.619%, eas); Associated with exostoses, multiple, type 2.

What condition is associated with EXT2 p.Arg299His (c.896G>A)?

EXT2 p.Arg299His (c.896G>A) is associated with exostoses, multiple, type 2 (ClinVar).

How common is EXT2 p.Arg299His (c.896G>A) in the general population?

EXT2 p.Arg299His (c.896G>A) is rare (popmax 0.619%, eas) (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.Arg299His (c.896G>A)?

AlphaMissense predicts ambiguous (score 0.3585) — an in-silico prediction, not a clinical call.

EXT2 p.Arg299His

c.896G>A · rs76901081 · VCV134214

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.3585 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.619%, eas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

exostoses, multiple, type 2

Computational evidence

Protein change
AlphaMissense	0.3585	ambiguous
REVEL	0.855	moderately pathogenic-leaning
SaProt	LLR -11.97	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.6, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 99 kb · p 0.085 · regional, not allelic
Overall
CADD	32.0	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 0.619% East Asian · 278/44,886 alleles

Filtering AF 0.559% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.536%

Overall 0.025% 404/1,613,646 alleles · rare exomes 369/1,461,384 · genomes 35/152,262 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.619%	161
South Asian	0.0417%	2,396
Remaining individualsnot grpmax-eligible	0.024%	4,164
European (non-Finnish)	0.00576%	17,353
Admixed American	0.005%	20,009
African / African-American	0.00267%	37,501

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.Arg299His
Coding: c.896G>A
MANE Select: NM_207122
dbSNP: rs76901081
Type: single nucleotide variant
Location: chr11:44124941 (GRCh38)
Gene constraint: LOEUF 0.775 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 87.59 · 6 PDB
Residue 299: a β-strand

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.Arg299Cys Uncertain significance ★★ ⚠ same residue
EXT2 p.Arg299Leu Uncertain significance ★ ⚠ 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-arg299his (accessed [today's date]).

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