Is IQSEC2 p.Arg200Pro (c.599G>C) pathogenic?

IQSEC2 p.Arg200Pro (c.599G>C) is classified Uncertain significance in IQSEC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2016-04-11). AlphaMissense: ambiguous (0.342); Absent from gnomAD v4.1; Associated with specific learning disability.

What condition is associated with IQSEC2 p.Arg200Pro (c.599G>C)?

IQSEC2 p.Arg200Pro (c.599G>C) is associated with specific learning disability (ClinVar).

How common is IQSEC2 p.Arg200Pro (c.599G>C) in the general population?

IQSEC2 p.Arg200Pro (c.599G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about IQSEC2 p.Arg200Pro (c.599G>C)?

AlphaMissense predicts ambiguous (score 0.342) — an in-silico prediction, not a clinical call.

IQSEC2 p.Arg200Pro

c.599G>C · rs1057519497 · VCV375456

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.342 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

specific learning disability

Computational evidence

Protein change
AlphaMissense	0.342	ambiguous
REVEL	0.131	moderately benign-leaning
SaProt	LLR -6.25	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.7	GERP 1.6, phastCons 1
Regional constraint	o/e 0.62	unconstrained · MANE · 683 bp · p 3.4e-08 · regional, not allelic
Overall
CADD	23.5	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.Arg200Pro
Coding: c.599G>C
MANE Select: NM_001111125
dbSNP: rs1057519497
Type: single nucleotide variant
Location: chrX:53320525 (GRCh38)
Structure: AlphaFold pLDDT 54.46 · 2 PDB
Residue 200: the 'disordered' region

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

Disease context

specific learning disability — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

IQSEC2 p.Arg200= Uncertain significance ★ same residue
IQSEC2 p.Arg200Gly Likely benign ★ same residue
IQSEC2 p.Arg1069Gln Uncertain significance ★★ ⚠ same condition
IQSEC2 c.2459+21C>T Pathogenic ★★ same type
IQSEC2 c.2889+1G>A Pathogenic ★★ same type
IQSEC2 p.Ala836Val Pathogenic/Likely pathogenic ★★ same type
IQSEC2 p.Arg1055Ter Pathogenic ★★ same type
IQSEC2 p.Arg1145Ter Pathogenic ★★ same type

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-arg200pro (accessed [today's date]).

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