Is IQSEC2 p.Pro1281= (c.3843C>T) pathogenic?

IQSEC2 p.Pro1281= (c.3843C>T) is classified Likely benign in IQSEC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-25). Very rare (popmax 0.000117%, nfe); Associated with intellectual disability, X-linked 1.

What condition is associated with IQSEC2 p.Pro1281= (c.3843C>T)?

IQSEC2 p.Pro1281= (c.3843C>T) is associated with intellectual disability, X-linked 1 (ClinVar).

How common is IQSEC2 p.Pro1281= (c.3843C>T) in the general population?

IQSEC2 p.Pro1281= (c.3843C>T) is very rare (popmax 0.000117%, nfe) (gnomAD).

IQSEC2 p.Pro1281=

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.3843C>T · rs1352308032 · VCV1143081

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000117%, nfe)

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 4.2	GERP 0.77, phastCons 1
Overall
CADD	2.732	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000117% European (non-Finnish) · 1/857,585 alleles

Overall 9.73e-05% 1/1,028,057 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.Pro1281=
Coding: c.3843C>T
MANE Select: NM_001111125
dbSNP: rs1352308032
Type: single nucleotide variant
Location: chrX:53234843 (GRCh38)
Structure: AlphaFold pLDDT 54.46 · 2 PDB
Residue 1281: 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 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
IQSEC2 p.Arg855Ter 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-pro1281 (accessed [today's date]).

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