Is EXT1 p.Ala217Ser (c.649G>T) pathogenic?

EXT1 p.Ala217Ser (c.649G>T) is classified Uncertain significance in EXT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-02-26). AlphaMissense: ambiguous (0.5054); Very rare (popmax 8.47e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with EXT1 p.Ala217Ser (c.649G>T)?

EXT1 p.Ala217Ser (c.649G>T) is associated with Inborn genetic diseases (ClinVar).

How common is EXT1 p.Ala217Ser (c.649G>T) in the general population?

EXT1 p.Ala217Ser (c.649G>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about EXT1 p.Ala217Ser (c.649G>T)?

AlphaMissense predicts ambiguous (score 0.5054) — an in-silico prediction, not a clinical call.

EXT1 p.Ala217Ser

c.649G>T · VCV4840595

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5054 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5054	ambiguous
REVEL	0.913	moderately pathogenic-leaning
SaProt	LLR -12.43	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 6, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 280 kb · p 4.8e-06 · regional, not allelic
Overall
CADD	33.0	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 8.47e-05% European (non-Finnish) · 1/1,180,026 alleles

Overall 6.2e-05% 1/1,614,096 alleles · very rare exomes 1/1,461,830 · genomes 0/152,266 · joint denominator

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: EXT1
Protein: p.Ala217Ser
Coding: c.649G>T
MANE Select: NM_000127
Type: single nucleotide variant
Location: chr8:118110398 (GRCh38)
Gene constraint: LOEUF 0.339 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 84.67 · 6 PDB
Residue 217: a UniProt-annotated variant site (in isolated osteochondroma; somatic mutation); a UniProt-annotated variant site (in ext1); a β-strand

Full EXT1 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

Similar variants

EXT1 p.Ala217Val Uncertain significance ★ ⚠ same residue
EXT1 p.Ala217= Likely benign ★ same residue
EXT1 p.Trp68Ter Pathogenic ★★ same condition
EXT1 p.Ala689Thr Uncertain significance ★★ ⚠ same condition
EXT1 p.Arg37Lys Uncertain significance ★★ ⚠ same condition
EXT1 p.Asn555Asp Uncertain significance ★★ ⚠ same condition
EXT1 p.Asp52Tyr Uncertain significance ★★ ⚠ same condition
EXT1 p.Asp615Asn Uncertain significance ★★ 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/ext1-p-ala217ser (accessed [today's date]).

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