Is IQSEC2 p.Pro8fs (c.22_23del) pathogenic?

IQSEC2 p.Pro8fs (c.2223del) is classified Pathogenic in IQSEC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-28). Associated with intellectual disability, X-linked 1.

What condition is associated with IQSEC2 p.Pro8fs (c.22_23del)?

IQSEC2 p.Pro8fs (c.22_23del) is associated with intellectual disability, X-linked 1 (ClinVar).

IQSEC2 p.Pro8fs

Q: How is Severe intellectual disability-progressive postnatal microcephaly-midline stereotypic hand movements syndrome inherited?

Typically X-linked recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.22_23del · VCV4685456

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

Conditions

intellectual disability, X-linked 1

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 1 of 15
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.47	GERP -1.6, phastCons 0.054

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

Variant & gene context

Gene: IQSEC2
Protein: p.Pro8fs
Coding: c.22_23del
MANE Select: NM_001111125
Type: Deletion
Location: chrX:53321101 (GRCh38)
Structure: AlphaFold pLDDT 54.46 · 2 PDB

Full IQSEC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

intellectual disability, X-linked 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Severe intellectual disability-progressive postnatal microcephaly-midline stereotypic hand movements syndrome (Orphanet):

Inheritance: X-linked recessive
Onset: Infancy, Neonatal

Similar variants

IQSEC2 p.Pro8Arg Uncertain significance ★★ ⚠ same residue
IQSEC2 p.Pro8= Likely benign ★★ same residue
IQSEC2 p.Pro8Ser Uncertain significance ★ ⚠ same residue
IQSEC2 p.Gly283fs Pathogenic ★★ same condition
IQSEC2 p.Pro1292fs Pathogenic/Likely pathogenic ★★ same condition
IQSEC2 p.Pro1442fs Pathogenic/Likely pathogenic ★★ same condition
IQSEC2 p.Pro285fs Pathogenic ★★ same condition
IQSEC2 p.Pro529fs 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/iqsec2-p-pro8fs (accessed [today's date]).

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