Is IQSEC2 p.Pro1439= (c.4317C>T) pathogenic?

IQSEC2 p.Pro1439= (c.4317C>T) is classified Likely benign in IQSEC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-12). Ultra-rare (popmax 0.0612%, afr); Associated with intellectual disability, X-linked 1.

What condition is associated with IQSEC2 p.Pro1439= (c.4317C>T)?

IQSEC2 p.Pro1439= (c.4317C>T) is associated with intellectual disability, X-linked 1 (ClinVar).

How common is IQSEC2 p.Pro1439= (c.4317C>T) in the general population?

IQSEC2 p.Pro1439= (c.4317C>T) is ultra-rare (popmax 0.0612%, afr) (gnomAD).

IQSEC2 p.Pro1439=

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.4317C>T · rs1216934275 · VCV759728

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0612%, afr)

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 -0.084	GERP -2, phastCons 0.57
Overall
CADD	1.008	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0612% African / African-American · 16/26,163 alleles

Filtering AF 0.0383% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0312%

Overall 0.00394% 18/456,342 alleles · ultra-rare exomes 10/390,593 · genomes 8/65,749 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0612%	1,635
Remaining individualsnot grpmax-eligible	0.00984%	10,165

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.Pro1439=
Coding: c.4317C>T
MANE Select: NM_001111125
dbSNP: rs1216934275
Type: single nucleotide variant
Location: chrX:53234369 (GRCh38)
Structure: AlphaFold pLDDT 54.46 · 2 PDB
Residue 1439: 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-pro1439 (accessed [today's date]).

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