Is EXT1 p.Ser418fs (c.1250dup) pathogenic?

EXT1 p.Ser418fs (c.1250dup) is classified Likely pathogenic in EXT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-27). Associated with EXT1-related disorders.

What condition is associated with EXT1 p.Ser418fs (c.1250dup)?

EXT1 p.Ser418fs (c.1250dup) is associated with EXT1-related disorders (ClinVar).

EXT1 p.Ser418fs

c.1250dup · VCV4901502

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

Conditions

EXT1-related disorders

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 4 of 11
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Variant & gene context

Gene: EXT1
Protein: p.Ser418fs
Coding: c.1250dup
MANE Select: NM_000127
Type: Duplication
Location: chr8:117830263 (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

EXT1-related disorders

Similar variants

EXT1 p.Ala354fs Likely pathogenic ★ same condition
EXT1 p.Ser418Ter Pathogenic ★ same residue
EXT1 p.Trp68fs Pathogenic ★ same condition
EXT1 p.Val491fs Pathogenic ★ same condition
EXT1 p.Asn373fs Likely pathogenic same condition
EXT1 c.1633-2A>G Pathogenic ★★ same condition
EXT1 c.1722+1G>A Pathogenic ★★ same condition
EXT1 c.1723-1G>C 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/ext1-p-ser418fs (accessed [today's date]).

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