Is IQSEC2 p.Pro984= (c.2952A>C) pathogenic?

IQSEC2 p.Pro984= (c.2952A>C) is classified Benign/Likely benign in IQSEC2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-11-17). Ultra-rare (popmax 0.0229%, mid); Associated with intellectual disability, X-linked 1.

What condition is associated with IQSEC2 p.Pro984= (c.2952A>C)?

IQSEC2 p.Pro984= (c.2952A>C) is associated with intellectual disability, X-linked 1 (ClinVar).

How common is IQSEC2 p.Pro984= (c.2952A>C) in the general population?

IQSEC2 p.Pro984= (c.2952A>C) is ultra-rare (popmax 0.0229%, mid) (gnomAD).

IQSEC2 p.Pro984=

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.2952A>C · rs782760727 · VCV509522

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0229%, 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	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.77	GERP 0.09, phastCons 1
Overall
CADD	11.61	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0229% Middle Eastern · 1/4,372 alleles

Filtering AF 0.00609% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00557%

Overall 0.0105% 127/1,209,475 alleles · ultra-rare exomes 113/1,097,544 · genomes 14/111,931 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.218%	459
Middle Easterngrpmax	0.0229%	4,372
Remaining individualsnot grpmax-eligible	0.0189%	5,287
European (non-Finnish)	0.0076%	13,160
African / African-American	0.00175%	57,114

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro984=
Coding: c.2952A>C
MANE Select: NM_001111125
dbSNP: rs782760727
Type: single nucleotide variant
Location: chrX:53241847 (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 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-pro984 (accessed [today's date]).

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