Is EXT1 p.Ile556Val (c.1666A>G) pathogenic?

EXT1 p.Ile556Val (c.1666A>G) is classified Uncertain significance in EXT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-16). AlphaMissense: likely benign (0.1164); Absent from gnomAD v4.1; Associated with chondrosarcoma.

What condition is associated with EXT1 p.Ile556Val (c.1666A>G)?

EXT1 p.Ile556Val (c.1666A>G) is associated with chondrosarcoma (ClinVar).

How common is EXT1 p.Ile556Val (c.1666A>G) in the general population?

EXT1 p.Ile556Val (c.1666A>G) is absent from gnomAD v4.1 (gnomAD).

How is Chondrosarcoma inherited?

Typically Not applicable, Unknown (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about EXT1 p.Ile556Val (c.1666A>G)?

AlphaMissense predicts likely benign (score 0.1164) — an in-silico prediction, not a clinical call.

EXT1 p.Ile556Val

c.1666A>G · rs2488096683 · VCV2675185

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1164 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

chondrosarcoma

Computational evidence

Protein change
AlphaMissense	0.1164	likely benign
REVEL	0.65	pathogenic-leaning
SaProt	LLR -8.97	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 5.1	GERP 1.7, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 17 kb · p 0.25 · regional, not allelic
Overall
CADD	23.9	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

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: EXT1
Protein: p.Ile556Val
Coding: c.1666A>G
MANE Select: NM_000127
dbSNP: rs2488096683
Type: single nucleotide variant
Location: chr8:117812928 (GRCh38)
Gene constraint: LOEUF 0.339 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 84.67 · 6 PDB

Full EXT1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

chondrosarcoma — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Chondrosarcoma (Orphanet):

Inheritance: Not applicable, Unknown
Onset: Adult
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

EXT1 p.Arg340Cys Pathogenic/Likely pathogenic ★★ same condition
EXT1 p.Arg340Leu Pathogenic ★★ same condition
EXT1 p.Gln2Ter Pathogenic ★★ same condition
EXT1 p.Ala689Thr Uncertain significance ★★ ⚠ same condition
EXT1 p.Arg188Ser Uncertain significance ★★ ⚠ same condition
EXT1 p.Arg325Trp Uncertain significance ★★ ⚠ same condition
EXT1 p.Arg384Lys Uncertain significance ★★ ⚠ same condition
EXT1 p.Arg691His 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-ile556val (accessed [today's date]).

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