Is EXT2 p.Asp666Tyr (c.1996G>T) pathogenic?

EXT2 p.Asp666Tyr (c.1996G>T) is classified Uncertain significance in EXT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-03). AlphaMissense: likely pathogenic (0.9828); Absent from gnomAD v4.1.

How common is EXT2 p.Asp666Tyr (c.1996G>T) in the general population?

EXT2 p.Asp666Tyr (c.1996G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about EXT2 p.Asp666Tyr (c.1996G>T)?

AlphaMissense predicts likely pathogenic (score 0.9828) — an in-silico prediction, not a clinical call.

EXT2 p.Asp666Tyr

c.1996G>T · rs1441921649 · VCV1319682

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9828 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9828	likely pathogenic
REVEL	0.695	pathogenic-leaning
SaProt	LLR -14.18	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.62	unconstrained · MANE · 37 kb · p 3.2e-09 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: EXT2
Protein: p.Asp666Tyr
Coding: c.1996G>T
MANE Select: NM_207122
dbSNP: rs1441921649
Type: single nucleotide variant
Location: chr11:44236353 (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

Similar variants

EXT2 c.1079+1G>A Pathogenic ★★ same type
EXT2 c.1079+1G>T Pathogenic ★★ same type
EXT2 c.1173+1G>A Pathogenic ★★ same type
EXT2 c.1662+1G>C Likely pathogenic ★★ same type
EXT2 c.536+1G>A Pathogenic ★★ same type
EXT2 c.626+1G>A Pathogenic ★★ same type
EXT2 c.626+1G>C Pathogenic ★★ same type
EXT2 c.626+1G>T Pathogenic/Likely pathogenic ★★ same type

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-asp666tyr (accessed [today's date]).

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