Is EXT2 p.Val638Ile (c.1912G>A) pathogenic?

EXT2 p.Val638Ile (c.1912G>A) is classified Conflicting classifications of pathogenicity in EXT2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-11-23). AlphaMissense: likely benign (0.0679); Ultra-rare (popmax 0.1%, afr); Associated with exostoses, multiple, type 2.

What condition is associated with EXT2 p.Val638Ile (c.1912G>A)?

EXT2 p.Val638Ile (c.1912G>A) is associated with exostoses, multiple, type 2 (ClinVar).

How common is EXT2 p.Val638Ile (c.1912G>A) in the general population?

EXT2 p.Val638Ile (c.1912G>A) is ultra-rare (popmax 0.1%, 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.Val638Ile (c.1912G>A)?

AlphaMissense predicts likely benign (score 0.0679) — an in-silico prediction, not a clinical call.

EXT2 p.Val638Ile

c.1912G>A · rs145024832 · VCV1556315

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0679 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.1%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

exostoses, multiple, type 2

Computational evidence

Protein change
AlphaMissense	0.0679	likely benign
REVEL	0.272	benign-leaning
SaProt	LLR -7.97	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.1, phastCons 1
Regional constraint	o/e 0.62	unconstrained · MANE · 37 kb · p 3.2e-09 · regional, not allelic
Overall
CADD	20.5	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 0.1% African / African-American · 75/75,036 alleles

Filtering AF 0.0817% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.075%

Overall 0.00669% 108/1,614,050 alleles · ultra-rare exomes 63/1,461,778 · genomes 45/152,272 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.1%	1,000
Middle Eastern	0.0165%	6,060
South Asian	0.00659%	15,179
European (non-Finnish)	0.00212%	47,199
Remaining individualsnot grpmax-eligible	0.0016%	62,500

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.Val638Ile
Coding: c.1912G>A
MANE Select: NM_207122
dbSNP: rs145024832
Type: single nucleotide variant
Location: chr11:44234220 (GRCh38)
Gene constraint: LOEUF 0.775 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 87.59 · 6 PDB
Residue 638: an α-helix

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 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-val638ile (accessed [today's date]).

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