Is EXT2 p.Ala642Thr (c.1924G>A) pathogenic?

EXT2 p.Ala642Thr (c.1924G>A) is classified Uncertain significance in EXT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-01). AlphaMissense: ambiguous (0.4241); Very rare (popmax 0.000254%, nfe); Associated with exostoses, multiple, type 2.

What condition is associated with EXT2 p.Ala642Thr (c.1924G>A)?

EXT2 p.Ala642Thr (c.1924G>A) is associated with exostoses, multiple, type 2 (ClinVar).

How common is EXT2 p.Ala642Thr (c.1924G>A) in the general population?

EXT2 p.Ala642Thr (c.1924G>A) is very rare (popmax 0.000254%, 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.Ala642Thr (c.1924G>A)?

AlphaMissense predicts ambiguous (score 0.4241) — an in-silico prediction, not a clinical call.

EXT2 p.Ala642Thr

c.1924G>A · rs2539783846 · VCV2675227

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4241 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Conditions

exostoses, multiple, type 2

Computational evidence

Protein change
AlphaMissense	0.4241	ambiguous
REVEL	0.463	indeterminate
SaProt	LLR -7.67	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 0.62	unconstrained · MANE · 37 kb · p 3.2e-09 · regional, not allelic
Overall
CADD	26.4	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 0.000254% European (non-Finnish) · 3/1,179,984 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,614,052 alleles · very rare exomes 3/1,461,728 · genomes 0/152,324 · 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.Ala642Thr
Coding: c.1924G>A
MANE Select: NM_207122
dbSNP: rs2539783846
Type: single nucleotide variant
Location: chr11:44234232 (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.Ala642= 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
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-ala642thr (accessed [today's date]).

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