Is IQSEC2 p.Asp565= (c.1695C>T) pathogenic?

IQSEC2 p.Asp565= (c.1695C>T) is classified Conflicting classifications of pathogenicity in IQSEC2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-08-02). Ultra-rare (popmax 0.0917%, mid); Associated with intellectual disability, X-linked 1.

What condition is associated with IQSEC2 p.Asp565= (c.1695C>T)?

IQSEC2 p.Asp565= (c.1695C>T) is associated with intellectual disability, X-linked 1 (ClinVar).

How common is IQSEC2 p.Asp565= (c.1695C>T) in the general population?

IQSEC2 p.Asp565= (c.1695C>T) is ultra-rare (popmax 0.0917%, mid) (gnomAD).

IQSEC2 p.Asp565=

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.1695C>T · rs886044781 · VCV281871

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0917%, mid)

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	<0.2	all four deltas below 0.2 · G>T here scores Δ0.24 · evaluated, not missing
Constraint at this position
Conservation	phyloP 1.4	GERP -2.8, phastCons 1
Overall
CADD	6.619	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0917% Middle Eastern · 4/4,361 alleles

Filtering AF 0.0313% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0189%

Overall 0.000662% 8/1,208,496 alleles · ultra-rare exomes 6/1,095,540 · genomes 2/112,956 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0917%	1,090
African / African-American	0.00174%	57,494
European (non-Finnish)	0.000336%	297,862

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.Asp565=
Coding: c.1695C>T
MANE Select: NM_001111125
dbSNP: rs886044781
Type: single nucleotide variant
Location: chrX:53250881 (GRCh38)
Structure: AlphaFold pLDDT 54.46 · 2 PDB
Residue 565: 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-asp565 (accessed [today's date]).

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