Is IQSEC2 p.Arg838= (c.2514G>T) pathogenic?

IQSEC2 p.Arg838= (c.2514G>T) is classified Uncertain significance in IQSEC2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-06-17). Very rare (popmax 0.00101%, nfe); Associated with intellectual disability, X-linked 1.

What condition is associated with IQSEC2 p.Arg838= (c.2514G>T)?

IQSEC2 p.Arg838= (c.2514G>T) is associated with intellectual disability, X-linked 1 (ClinVar).

How common is IQSEC2 p.Arg838= (c.2514G>T) in the general population?

IQSEC2 p.Arg838= (c.2514G>T) is very rare (popmax 0.00101%, nfe) (gnomAD).

IQSEC2 p.Arg838=

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.2514G>T · rs1167090163 · VCV851029

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00101%, nfe)

Conditions

intellectual disability, X-linked 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.85	donor gain, 2 bp away · masked 0 · deltas
Pangolin	Δ0.40	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 0.14	GERP 2.1, phastCons 0.94
Overall
CADD	22.0	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00101% European (non-Finnish) · 9/894,266 alleles

Filtering AF 0.000473% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000343%

Overall 0.000745% 9/1,207,942 alleles · very rare exomes 6/1,096,512 · genomes 3/111,430 · joint denominator

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.Arg838=
Coding: c.2514G>T
MANE Select: NM_001111125
dbSNP: rs1167090163
Type: single nucleotide variant
Location: chrX:53248182 (GRCh38)
Structure: AlphaFold pLDDT 54.46 · 2 PDB
Residue 838: the sec7 domain; an α-helix

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 p.Arg838Gln 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.Arg531Ter Pathogenic/Likely pathogenic ★★ same condition
IQSEC2 p.Arg758Ter 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-arg838 (accessed [today's date]).

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