Is IQSEC2 p.Arg1069Pro (c.3206G>C) pathogenic?

IQSEC2 p.Arg1069Pro (c.3206G>C) is classified Conflicting classifications of pathogenicity in IQSEC2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2022-11-08). AlphaMissense: likely pathogenic (0.999); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with IQSEC2 p.Arg1069Pro (c.3206G>C)?

IQSEC2 p.Arg1069Pro (c.3206G>C) is associated with Inborn genetic diseases, intellectual disability, X-linked 1 (ClinVar).

How common is IQSEC2 p.Arg1069Pro (c.3206G>C) in the general population?

IQSEC2 p.Arg1069Pro (c.3206G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about IQSEC2 p.Arg1069Pro (c.3206G>C)?

AlphaMissense predicts likely pathogenic (score 0.999) — an in-silico prediction, not a clinical call.

IQSEC2 p.Arg1069Pro

c.3206G>C · rs782632137 · VCV449760

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.999 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.999	likely pathogenic · top 3% in IQSEC2
REVEL	0.538	indeterminate
SaProt	LLR -15.62	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.1, phastCons 1
Regional constraint	o/e 0.53	unconstrained · MANE · 13 kb · p 4.6e-24 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: IQSEC2
Protein: p.Arg1069Pro
Coding: c.3206G>C
MANE Select: NM_001111125
dbSNP: rs782632137
Type: single nucleotide variant
Location: chrX:53238216 (GRCh38)
Structure: AlphaFold pLDDT 54.46 · 2 PDB
Residue 1069: an α-helix

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.Arg1069Gln Uncertain significance ★★ ⚠ same residue
IQSEC2 p.Arg1069Trp Uncertain significance ★ ⚠ same residue
IQSEC2 p.Arg1069= 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

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-arg1069pro (accessed [today's date]).

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