Is EXT1 p.Leu166Ser (c.497T>C) pathogenic?

EXT1 p.Leu166Ser (c.497T>C) is classified Uncertain significance in EXT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-05). AlphaMissense: likely pathogenic (0.9928); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with EXT1 p.Leu166Ser (c.497T>C)?

EXT1 p.Leu166Ser (c.497T>C) is associated with Inborn genetic diseases (ClinVar).

How common is EXT1 p.Leu166Ser (c.497T>C) in the general population?

EXT1 p.Leu166Ser (c.497T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about EXT1 p.Leu166Ser (c.497T>C)?

AlphaMissense predicts likely pathogenic (score 0.9928) — an in-silico prediction, not a clinical call.

EXT1 p.Leu166Ser

c.497T>C · rs2488051788 · VCV2609574

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9928 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9928	likely pathogenic
REVEL	0.865	moderately pathogenic-leaning
SaProt	LLR -10.64	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 11	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

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: EXT1
Protein: p.Leu166Ser
Coding: c.497T>C
MANE Select: NM_000127
dbSNP: rs2488051788
Type: single nucleotide variant
Location: chr8:118110550 (GRCh38)
Gene constraint: LOEUF 0.339 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 84.67 · 6 PDB
Residue 166: a binding site

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.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
EXT1 p.Glu38Gly Uncertain significance ★★ ⚠ same condition
EXT1 p.Glu413Asp 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-leu166ser (accessed [today's date]).

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