Is IQSEC2 p.Pro656fs (c.1967del) pathogenic?

IQSEC2 p.Pro656fs (c.1967del) is classified Pathogenic in IQSEC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-05-28). No allele count reported in gnomAD v4.1 (AN 1,208,369); Associated with intellectual disability, X-linked 1.

What condition is associated with IQSEC2 p.Pro656fs (c.1967del)?

IQSEC2 p.Pro656fs (c.1967del) is associated with intellectual disability, X-linked 1 (ClinVar).

How common is IQSEC2 p.Pro656fs (c.1967del) in the general population?

IQSEC2 p.Pro656fs (c.1967del) is no allele count reported in gnomAD v4.1 (AN 1,208,369) (gnomAD).

IQSEC2 p.Pro656fs

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.1967del · rs1602283534 · VCV804003

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,208,369)

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 5 of 15
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 2.2	GERP 1.9, phastCons 1
Region caveats
Repeat context	tandem	G-rich low complexity · ambiguous alignment · confidence, not pathogenicity

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

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,208,369). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: IQSEC2
Protein: p.Pro656fs
Coding: c.1967del
MANE Select: NM_001111125
dbSNP: rs1602283534
Type: Deletion
Location: chrX:53250609 (GRCh38)
Structure: AlphaFold pLDDT 54.46 · 2 PDB
Residue 656: 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.Pro285fs 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

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-pro656fs (accessed [today's date]).

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