Is IQSEC2 p.Arg1069Gln (c.3206G>A) pathogenic?

IQSEC2 p.Arg1069Gln (c.3206G>A) is classified Uncertain significance in IQSEC2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-04-05). AlphaMissense: likely pathogenic (0.6891); Very rare (popmax 0.00246%, nfe); Associated with intellectual disability, X-linked 1.

What condition is associated with IQSEC2 p.Arg1069Gln (c.3206G>A)?

IQSEC2 p.Arg1069Gln (c.3206G>A) is associated with intellectual disability, X-linked 1, specific learning disability (ClinVar).

How common is IQSEC2 p.Arg1069Gln (c.3206G>A) in the general population?

IQSEC2 p.Arg1069Gln (c.3206G>A) is very rare (popmax 0.00246%, nfe) (gnomAD).

What do computational predictors say about IQSEC2 p.Arg1069Gln (c.3206G>A)?

AlphaMissense predicts likely pathogenic (score 0.6891) — an in-silico prediction, not a clinical call.

IQSEC2 p.Arg1069Gln

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.3206G>A · rs782632137 · VCV975246

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.6891 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00246%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

intellectual disability, X-linked 1

Computational evidence

Protein change
AlphaMissense	0.6891	likely pathogenic
REVEL	0.367	indeterminate
SaProt	LLR -7.69	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.1, phastCons 1
Regional constraint	o/e 0.53	unconstrained · MANE · 13 kb · p 4.6e-24 · regional, not allelic
Overall
CADD	29.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00246% European (non-Finnish) · 22/894,664 alleles

Filtering AF 0.00161% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00137%

Overall 0.00199% 24/1,208,239 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00246%	40,667
Finnishnot grpmax-eligible	0.00215%	46,453
Remaining individualsnot grpmax-eligible	0.0021%	47,552

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.Arg1069Gln
Coding: c.3206G>A
MANE Select: NM_001111125
dbSNP: rs782632137
Type: single nucleotide variant
Location: chrX:53238216 (GRCh38)
Structure: AlphaFold pLDDT 54.46 · 2 PDB
Residue 1069: an α-helix

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

Also linked: specific learning disability

For Severe intellectual disability-progressive postnatal microcephaly-midline stereotypic hand movements syndrome (Orphanet):

Inheritance: X-linked recessive
Onset: Infancy, Neonatal

Similar variants

IQSEC2 p.Arg1069Pro Conflicting classifications of pathogenicity ★ ⚠ same residue
IQSEC2 p.Arg1069Trp Uncertain significance ★ ⚠ same residue
IQSEC2 p.Arg1069= Uncertain significance ★ 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

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-arg1069gln (accessed [today's date]).

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