Is IQSEC2 p.Pro285fs (c.854del) pathogenic?

IQSEC2 p.Pro285fs (c.854del) is classified Pathogenic in IQSEC2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-10-30). Very rare (popmax 0.0018%, sas); Associated with intellectual disability, X-linked 1.

What condition is associated with IQSEC2 p.Pro285fs (c.854del)?

IQSEC2 p.Pro285fs (c.854del) is associated with intellectual disability, X-linked 1 (ClinVar).

How common is IQSEC2 p.Pro285fs (c.854del) in the general population?

IQSEC2 p.Pro285fs (c.854del) is very rare (popmax 0.0018%, sas) (gnomAD).

IQSEC2 p.Pro285fs

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.854del · rs782460038 · VCV619985

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0018%, sas)

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 3 of 15
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 5	GERP 0.67, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0018% South Asian · 1/55,476 alleles

Overall 9.21e-05% 1/1,086,077 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: IQSEC2
Protein: p.Pro285fs
Coding: c.854del
MANE Select: NM_001111125
dbSNP: rs782460038
Type: Deletion
Location: chrX:53255945 (GRCh38)
Structure: AlphaFold pLDDT 54.46 · 2 PDB
Residue 285: the 'disordered' region

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.Gly283fs Pathogenic ★★ same condition
IQSEC2 p.Pro1292fs Pathogenic/Likely pathogenic ★★ same condition
IQSEC2 p.Pro1442fs Pathogenic/Likely pathogenic ★★ same condition
IQSEC2 p.Pro529fs Pathogenic ★★ same condition
IQSEC2 p.Pro559fs Pathogenic ★★ same condition
IQSEC2 p.Ser277fs Pathogenic ★★ same condition
IQSEC2 p.Tyr269fs Pathogenic ★★ same condition
IQSEC2 p.Ala1313_Val1316del 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/iqsec2-p-pro285fs (accessed [today's date]).

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