Is EXT2 p.Thr219Met (c.656C>T) pathogenic?

EXT2 p.Thr219Met (c.656C>T) is classified Conflicting classifications of pathogenicity in EXT2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-05-14). AlphaMissense: likely benign (0.2534); Very rare (popmax 0.01%, amr); Associated with Inborn genetic diseases.

What condition is associated with EXT2 p.Thr219Met (c.656C>T)?

EXT2 p.Thr219Met (c.656C>T) is associated with Inborn genetic diseases, exostoses, multiple, type 2 (ClinVar).

How common is EXT2 p.Thr219Met (c.656C>T) in the general population?

EXT2 p.Thr219Met (c.656C>T) is very rare (popmax 0.01%, amr) (gnomAD).

What do computational predictors say about EXT2 p.Thr219Met (c.656C>T)?

AlphaMissense predicts likely benign (score 0.2534) — an in-silico prediction, not a clinical call.

EXT2 p.Thr219Met

c.656C>T · rs202208526 · VCV658032

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2534 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.01%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2534	likely benign
REVEL	0.726	pathogenic-leaning
SaProt	LLR -9.32	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 99 kb · p 0.085 · regional, not allelic
Overall
CADD	32.0	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 0.01% Admixed American · 6/60,002 alleles

Filtering AF 0.00428% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.00118% 19/1,613,956 alleles · very rare exomes 17/1,461,820 · genomes 2/152,136 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.01%	10,000
African / African-American	0.00401%	24,967
Remaining individualsnot grpmax-eligible	0.0032%	31,244
Finnishnot grpmax-eligible	0.00156%	64,008
European (non-Finnish)	0.000593%	168,569

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.Thr219Met
Coding: c.656C>T
MANE Select: NM_207122
dbSNP: rs202208526
Type: single nucleotide variant
Location: chr11:44114214 (GRCh38)
Gene constraint: LOEUF 0.775 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 87.59 · 6 PDB
Residue 219: a β-strand

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: exostoses, multiple, type 2

Similar variants

EXT2 p.Thr219= Likely benign ★ same residue
EXT2 p.Thr219Ala Likely pathogenic ★ ⚠ 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

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-thr219met (accessed [today's date]).

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