Is IQSEC2 p.Pro483= (c.1449G>A) pathogenic?

IQSEC2 p.Pro483= (c.1449G>A) is classified Benign/Likely benign in IQSEC2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-10-28). Ultra-rare (popmax 0.023%, mid); Associated with Inborn genetic diseases.

What condition is associated with IQSEC2 p.Pro483= (c.1449G>A)?

IQSEC2 p.Pro483= (c.1449G>A) is associated with Inborn genetic diseases, intellectual disability, X-linked 1 (ClinVar).

How common is IQSEC2 p.Pro483= (c.1449G>A) in the general population?

IQSEC2 p.Pro483= (c.1449G>A) is ultra-rare (popmax 0.023%, mid) (gnomAD).

IQSEC2 p.Pro483=

c.1449G>A · rs200629644 · VCV390121

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.023%, mid)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.73	GERP -3.6, phastCons 0.052
Overall
CADD	2.678	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.023% Middle Eastern · 1/4,354 alleles

Filtering AF 0.00419% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00377%

Overall 0.00455% 55/1,209,839 alleles · ultra-rare exomes 49/1,098,103 · genomes 6/111,736 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.023%	4,354
European (non-Finnish)	0.00547%	18,268
African / African-American	0.0035%	28,568
Admixed American	0.00218%	45,811
Remaining individualsnot grpmax-eligible	0.0021%	47,616
South Asian	0.00176%	56,772

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.Pro483=
Coding: c.1449G>A
MANE Select: NM_001111125
dbSNP: rs200629644
Type: single nucleotide variant
Location: chrX:53251127 (GRCh38)
Structure: AlphaFold pLDDT 54.46 · 2 PDB
Residue 483: the 'disordered' region

Full IQSEC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: intellectual disability, X-linked 1

Similar variants

IQSEC2 p.Pro483Leu 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
IQSEC2 p.Arg359His Likely pathogenic ★★ same condition
IQSEC2 p.Arg531Ter Pathogenic/Likely 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-pro483 (accessed [today's date]).

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