Is EXT2 p.Arg322His (c.965G>A) pathogenic?

EXT2 p.Arg322His (c.965G>A) is classified Conflicting classifications of pathogenicity in EXT2 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-05-01). AlphaMissense: ambiguous (0.4074); Ultra-rare (popmax 0.0267%, nfe); Associated with exostoses, multiple, type 2.

What condition is associated with EXT2 p.Arg322His (c.965G>A)?

EXT2 p.Arg322His (c.965G>A) is associated with exostoses, multiple, type 2 (ClinVar).

How common is EXT2 p.Arg322His (c.965G>A) in the general population?

EXT2 p.Arg322His (c.965G>A) is ultra-rare (popmax 0.0267%, 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.Arg322His (c.965G>A)?

AlphaMissense predicts ambiguous (score 0.4074) — an in-silico prediction, not a clinical call.

EXT2 p.Arg322His

c.965G>A · rs149727518 · VCV304583

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

ambiguous

0.4074 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0267%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

exostoses, multiple, type 2

Computational evidence

Protein change
AlphaMissense	0.4074	ambiguous
REVEL	0.91	moderately pathogenic-leaning
SaProt	LLR -12.16	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 1.6, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 99 kb · p 0.085 · regional, not allelic
Overall
CADD	33.0	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 0.0267% European (non-Finnish) · 315/1,180,038 alleles

Filtering AF 0.0243% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0233%

Overall 0.0397% 641/1,614,038 alleles · ultra-rare exomes 532/1,461,890 · genomes 109/152,148 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.405%	247
Finnishnot grpmax-eligible	0.278%	360
Remaining individualsnot grpmax-eligible	0.0288%	3,472
European (non-Finnish)grpmax	0.0267%	3,746
Admixed American	0.015%	6,667
South Asian	0.0011%	91,074

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg322His
Coding: c.965G>A
MANE Select: NM_207122
dbSNP: rs149727518
Type: single nucleotide variant
Location: chr11:44126841 (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.Arg322Cys 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
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-arg322his (accessed [today's date]).

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