Is EXT2 p.Met42Val (c.124A>G) pathogenic?

EXT2 p.Met42Val (c.124A>G) is classified Benign/Likely benign in EXT2 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-01-26). AlphaMissense: likely benign (0.0649); Low-frequency (popmax 4.86%, afr); Associated with exostoses, multiple, type 1.

What condition is associated with EXT2 p.Met42Val (c.124A>G)?

EXT2 p.Met42Val (c.124A>G) is associated with exostoses, multiple, type 1, exostoses, multiple, type 2 (ClinVar).

How common is EXT2 p.Met42Val (c.124A>G) in the general population?

EXT2 p.Met42Val (c.124A>G) is low-frequency (popmax 4.86%, 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.Met42Val (c.124A>G)?

AlphaMissense predicts likely benign (score 0.0649) — an in-silico prediction, not a clinical call.

EXT2 p.Met42Val

c.124A>G · rs4755779 · VCV134207

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.0649 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 4.86%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

exostoses, multiple, type 1

Computational evidence

Protein change
AlphaMissense	0.0649	likely benign
REVEL	0.161	moderately benign-leaning
SaProt	LLR -3.76	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.44	GERP -4.7, phastCons 0.82
Regional constraint	o/e 0.93	unconstrained · MANE · 99 kb · p 0.085 · regional, not allelic
Overall
CADD	8.182	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 4.86% African / African-American · 3,645/74,992 alleles

Filtering AF 4.73% ClinGen BA1/BS1 input FAF95, joint · FAF99 4.68%

Overall 0.251% 4,048/1,614,112 alleles · low-frequency exomes 1,988/1,461,894 · genomes 2,060/152,218 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	4.86%	21
Remaining individualsnot grpmax-eligible	0.269%	372
Admixed American	0.238%	420
Middle Eastern	0.099%	1,010
South Asian	0.011%	9,108
European (non-Finnish)	0.00636%	15,734
East Asian	0.00223%	44,866

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.Met42Val
Coding: c.124A>G
MANE Select: NM_207122
dbSNP: rs4755779
Type: single nucleotide variant
Location: chr11:44107836 (GRCh38)
Gene constraint: LOEUF 0.775 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 87.59 · 6 PDB
Residue 42: a UniProt-annotated variant site (in)

Full EXT2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

exostoses, multiple, type 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: exostoses, multiple, type 2

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-met42val (accessed [today's date]).

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