Is IQSEC2 p.Arg207Cys (c.619C>T) pathogenic?

IQSEC2 p.Arg207Cys (c.619C>T) is classified Uncertain significance in IQSEC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-07-14). AlphaMissense: likely pathogenic (0.8807); Very rare (popmax 0.000459%, nfe); Associated with intellectual disability, X-linked 1.

What condition is associated with IQSEC2 p.Arg207Cys (c.619C>T)?

IQSEC2 p.Arg207Cys (c.619C>T) is associated with intellectual disability, X-linked 1 (ClinVar).

How common is IQSEC2 p.Arg207Cys (c.619C>T) in the general population?

IQSEC2 p.Arg207Cys (c.619C>T) is very rare (popmax 0.000459%, nfe) (gnomAD).

What do computational predictors say about IQSEC2 p.Arg207Cys (c.619C>T)?

AlphaMissense predicts likely pathogenic (score 0.8807) — an in-silico prediction, not a clinical call.

IQSEC2 p.Arg207Cys

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.619C>T · rs1295281780 · VCV2191128

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8807 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000459%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

intellectual disability, X-linked 1

Computational evidence

Protein change
AlphaMissense	0.8807	likely pathogenic
REVEL	0.209	benign-leaning
SaProt	LLR -8.36	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.4, phastCons 1
Regional constraint	o/e 0.62	unconstrained · MANE · 683 bp · p 3.4e-08 · regional, not allelic
Overall
CADD	27.8	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

Grpmax group 0.000459% European (non-Finnish) · 4/870,534 alleles

Filtering AF 0.000108% ClinGen BA1/BS1 input FAF95, joint · FAF99 7.3e-05%

Overall 0.000431% 5/1,160,570 alleles · very rare exomes 4/1,047,727 · genomes 1/112,843 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00219%	45,574
European (non-Finnish)grpmax	0.000459%	217,634

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg207Cys
Coding: c.619C>T
MANE Select: NM_001111125
dbSNP: rs1295281780
Type: single nucleotide variant
Location: chrX:53320505 (GRCh38)
Structure: AlphaFold pLDDT 54.46 · 2 PDB
Residue 207: the 'disordered' region

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.Arg207His Uncertain significance ★ ⚠ same residue
IQSEC2 p.Arg207Ser 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.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-arg207cys (accessed [today's date]).

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