Is IQSEC2 p.Arg6fs (c.15del) pathogenic?

IQSEC2 p.Arg6fs (c.15del) is classified Likely pathogenic in IQSEC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-20). Very rare (popmax 0.00362%, afr); Associated with intellectual disability, X-linked 1.

What condition is associated with IQSEC2 p.Arg6fs (c.15del)?

IQSEC2 p.Arg6fs (c.15del) is associated with intellectual disability, X-linked 1 (ClinVar).

How common is IQSEC2 p.Arg6fs (c.15del) in the general population?

IQSEC2 p.Arg6fs (c.15del) is very rare (popmax 0.00362%, afr) (gnomAD).

IQSEC2 p.Arg6fs

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.15del · rs1556870861 · VCV3251989

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00362%, afr)

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-escape possible for C-terminal truncations
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 3.1	GERP 2.5, phastCons 0.74
Overall
CADD	15.54	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00362% African / African-American · 2/55,295 alleles

Filtering AF 0.0006% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000224%

Overall 0.000174% 2/1,146,144 alleles · very rare exomes 0/1,033,859 · genomes 2/112,285 · joint denominator

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.Arg6fs
Coding: c.15del
MANE Select: NM_001111125 · reported on NM_001243197
dbSNP: rs1556870861
Type: Deletion
Location: chrX:53281507 (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.Gly6= Benign ★ same residue
IQSEC2 p.Gly6Arg Likely benign ★ 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
IQSEC2 p.Pro559fs 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-arg6fs (accessed [today's date]).

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