Is EXT2 p.Phe352Leu (c.1056C>G) pathogenic?

EXT2 p.Phe352Leu (c.1056C>G) is classified Uncertain significance in EXT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-25). AlphaMissense: likely pathogenic (0.9149); Absent from gnomAD v4.1; Associated with EXT2-related disorder.

What condition is associated with EXT2 p.Phe352Leu (c.1056C>G)?

EXT2 p.Phe352Leu (c.1056C>G) is associated with EXT2-related disorder (ClinVar).

How common is EXT2 p.Phe352Leu (c.1056C>G) in the general population?

EXT2 p.Phe352Leu (c.1056C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about EXT2 p.Phe352Leu (c.1056C>G)?

AlphaMissense predicts likely pathogenic (score 0.9149) — an in-silico prediction, not a clinical call.

EXT2 p.Phe352Leu

c.1056C>G · rs150255775 · VCV2632452

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9149 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

EXT2-related disorder

Computational evidence

Protein change
AlphaMissense	0.9149	likely pathogenic
REVEL	0.869	moderately pathogenic-leaning
SaProt	LLR -10.15	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 1.2	GERP -0.52, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 99 kb · p 0.085 · regional, not allelic
Overall
CADD	24.3	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.Phe352Leu
Coding: c.1056C>G
MANE Select: NM_207122
dbSNP: rs150255775
Type: single nucleotide variant
Location: chr11:44126932 (GRCh38)
Gene constraint: LOEUF 0.775 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 87.59 · 6 PDB
Residue 352: a turn

Full EXT2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

EXT2-related disorder

Similar variants

EXT2 p.Phe352= Likely benign ★ same residue
EXT2 c.1173+1G>A Pathogenic ★★ same condition
EXT2 c.744-2A>C Pathogenic ★★ same condition
EXT2 p.Gln172Ter Pathogenic ★★ same condition
EXT2 p.Tyr222Ter Pathogenic ★★ same condition
EXT2 p.Tyr348Ter Pathogenic/Likely pathogenic ★★ same condition
EXT2 c.939+1G>A Pathogenic ★ same condition
EXT2 p.Arg266Ter Likely 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/ext2-p-phe352leu (accessed [today's date]).

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