Is EXT2 p.His571Arg (c.1712A>G) pathogenic?

EXT2 p.His571Arg (c.1712A>G) is classified Uncertain significance in EXT2 (ClinVar, Single submitter, 2 submitters; last evaluated 2023-10-30). AlphaMissense: likely pathogenic (0.998); Very rare (popmax 0.00267%, afr); Associated with exostoses, multiple, type 2.

What condition is associated with EXT2 p.His571Arg (c.1712A>G)?

EXT2 p.His571Arg (c.1712A>G) is associated with exostoses, multiple, type 2 (ClinVar).

How common is EXT2 p.His571Arg (c.1712A>G) in the general population?

EXT2 p.His571Arg (c.1712A>G) is very rare (popmax 0.00267%, afr) (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.His571Arg (c.1712A>G)?

AlphaMissense predicts likely pathogenic (score 0.998) — an in-silico prediction, not a clinical call.

EXT2 p.His571Arg

c.1712A>G · rs150392363 · VCV134203

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.998 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

exostoses, multiple, type 2

Computational evidence

Protein change
AlphaMissense	0.998	likely pathogenic · top 6% in EXT2
REVEL	0.92	moderately pathogenic-leaning
SaProt	LLR -16.06	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.2, phastCons 1
Regional constraint	o/e 0.62	unconstrained · MANE · 37 kb · p 3.2e-09 · regional, not allelic
Overall
CADD	26.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00267% African / African-American · 2/75,016 alleles

Filtering AF 0.000442% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000496% 8/1,614,056 alleles · very rare exomes 5/1,461,814 · genomes 3/152,242 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,250
African / African-Americangrpmax	0.00267%	37,508
South Asian	0.0011%	91,070
European (non-Finnish)	0.000254%	393,334

Remaining individuals 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.His571Arg
Coding: c.1712A>G
MANE Select: NM_207122
dbSNP: rs150392363
Type: single nucleotide variant
Location: chr11:44232402 (GRCh38)
Gene constraint: LOEUF 0.775 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 87.59 · 6 PDB
Residue 571: 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.His571Pro 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-his571arg (accessed [today's date]).

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