Is EXT2 p.Val363Met (c.1087G>A) pathogenic?

EXT2 p.Val363Met (c.1087G>A) is classified Conflicting classifications of pathogenicity in EXT2 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-02-20). AlphaMissense: likely benign (0.1615); Rare (popmax 0.106%, nfe); Associated with EXT2-related disorder.

What condition is associated with EXT2 p.Val363Met (c.1087G>A)?

EXT2 p.Val363Met (c.1087G>A) is associated with EXT2-related disorder, exostoses, multiple, type 1, exostoses, multiple, type 2 (ClinVar).

How common is EXT2 p.Val363Met (c.1087G>A) in the general population?

EXT2 p.Val363Met (c.1087G>A) is rare (popmax 0.106%, nfe) (gnomAD).

What do computational predictors say about EXT2 p.Val363Met (c.1087G>A)?

AlphaMissense predicts likely benign (score 0.1615) — an in-silico prediction, not a clinical call.

EXT2 p.Val363Met

c.1087G>A · rs138943091 · VCV304586

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.1615 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.106%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

EXT2-related disorder

Computational evidence

Protein change
AlphaMissense	0.1615	likely benign
REVEL	0.911	moderately pathogenic-leaning
SaProt	LLR -11.47	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.7, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 99 kb · p 0.085 · regional, not allelic
Overall
CADD	28.6	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 0.106% European (non-Finnish) · 1,245/1,179,822 alleles

Filtering AF 0.101% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0987%

Overall 0.084% 1,356/1,613,954 alleles · rare exomes 1,289/1,461,630 · genomes 67/152,324 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.106%	948
South Asian	0.0637%	1,570
Remaining individualsnot grpmax-eligible	0.0496%	2,016
Middle Eastern	0.033%	3,031
African / African-American	0.0187%	5,359
Admixed American	0.00833%	12,003
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606

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.Val363Met
Coding: c.1087G>A
MANE Select: NM_207122
dbSNP: rs138943091
Type: single nucleotide variant
Location: chr11:44130052 (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

EXT2-related disorder

Also linked: exostoses, multiple, type 1 exostoses, multiple, type 2

Similar variants

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
EXT2 c.626+1G>T Pathogenic/Likely 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-val363met (accessed [today's date]).

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