Is IQSEC2 p.Pro1223= (c.3669G>A) pathogenic?

IQSEC2 p.Pro1223= (c.3669G>A) is classified Likely benign in IQSEC2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-12-22). Rare (popmax 0.115%, amr); Associated with Inborn genetic diseases.

What condition is associated with IQSEC2 p.Pro1223= (c.3669G>A)?

IQSEC2 p.Pro1223= (c.3669G>A) is associated with Inborn genetic diseases, intellectual disability, X-linked 1 (ClinVar).

How common is IQSEC2 p.Pro1223= (c.3669G>A) in the general population?

IQSEC2 p.Pro1223= (c.3669G>A) is rare (popmax 0.115%, amr) (gnomAD).

IQSEC2 p.Pro1223=

c.3669G>A · rs782744933 · VCV387552

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

rare (popmax 0.115%, amr)

Conditions

Inborn genetic diseases

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 -0.96	GERP -3.7, phastCons 0.004
Overall
CADD	4.559	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.115% Admixed American · 43/37,422 alleles

Filtering AF 0.0876% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0781%

Overall 0.00598% 69/1,153,765 alleles · rare exomes 34/1,047,510 · genomes 35/106,255 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.115%	870
Remaining individualsnot grpmax-eligible	0.0353%	2,835
East Asian	0.0134%	7,471
South Asian	0.00383%	26,090
African / African-American	0.00186%	53,673
European (non-Finnish)	0.000346%	289,068

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.Pro1223=
Coding: c.3669G>A
MANE Select: NM_001111125
dbSNP: rs782744933
Type: single nucleotide variant
Location: chrX:53235017 (GRCh38)
Structure: AlphaFold pLDDT 54.46 · 2 PDB
Residue 1223: 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.Pro1223Gln Uncertain significance ★ ⚠ same residue
IQSEC2 p.Pro1223Leu Benign ★ 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

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-pro1223 (accessed [today's date]).

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