Is IQSEC2 p.Pro1445= (c.4335T>C) pathogenic?

IQSEC2 p.Pro1445= (c.4335T>C) is classified Likely benign in IQSEC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-01). Absent from gnomAD v4.1; Associated with intellectual disability, X-linked 1.

What condition is associated with IQSEC2 p.Pro1445= (c.4335T>C)?

IQSEC2 p.Pro1445= (c.4335T>C) is associated with intellectual disability, X-linked 1 (ClinVar).

How common is IQSEC2 p.Pro1445= (c.4335T>C) in the general population?

IQSEC2 p.Pro1445= (c.4335T>C) is absent from gnomAD v4.1 (gnomAD).

IQSEC2 p.Pro1445=

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.4335T>C · rs1602256403 · VCV712267

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 165,038)

Conditions

intellectual disability, X-linked 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.24	GERP -2.7, phastCons 0.95
Overall
CADD	4.351	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 165,038). 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.Pro1445=
Coding: c.4335T>C
MANE Select: NM_001111125
dbSNP: rs1602256403
Type: single nucleotide variant
Location: chrX:53234351 (GRCh38)
Structure: AlphaFold pLDDT 54.46 · 2 PDB
Residue 1445: 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.Pro1445fs Pathogenic ★ same residue
IQSEC2 c.2459+21C>T Pathogenic ★★ same condition
IQSEC2 c.2889+1G>A Pathogenic ★★ same condition
IQSEC2 p.Ala836Val Pathogenic/Likely pathogenic ★★ same condition
IQSEC2 p.Arg1055Ter Pathogenic ★★ same condition
IQSEC2 p.Arg1145Ter Pathogenic ★★ same condition
IQSEC2 p.Arg531Ter Pathogenic/Likely pathogenic ★★ same condition
IQSEC2 p.Arg758Ter 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-pro1445 (accessed [today's date]).

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