Is IQSEC2 p.Arg207Ser (c.619C>A) pathogenic?

IQSEC2 p.Arg207Ser (c.619C>A) is classified Benign in IQSEC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-20). AlphaMissense: likely pathogenic (0.9138); Very rare (popmax 0.00505%, nfe); Associated with intellectual disability, X-linked 1.

What condition is associated with IQSEC2 p.Arg207Ser (c.619C>A)?

IQSEC2 p.Arg207Ser (c.619C>A) is associated with intellectual disability, X-linked 1 (ClinVar).

How common is IQSEC2 p.Arg207Ser (c.619C>A) in the general population?

IQSEC2 p.Arg207Ser (c.619C>A) is very rare (popmax 0.00505%, nfe) (gnomAD).

What do computational predictors say about IQSEC2 p.Arg207Ser (c.619C>A)?

AlphaMissense predicts likely pathogenic (score 0.9138) — an in-silico prediction, not a clinical call.

IQSEC2 p.Arg207Ser

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>A · rs1295281780 · VCV1169847

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9138 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00505%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

intellectual disability, X-linked 1

Computational evidence

Protein change
AlphaMissense	0.9138	likely pathogenic
REVEL	0.231	benign-leaning
SaProt	LLR -5.13	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	22.4	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 0.00505% European (non-Finnish) · 44/870,534 alleles

Filtering AF 0.00383% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00341%

Overall 0.00388% 45/1,160,570 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00505%	19,785
Remaining individualsnot grpmax-eligible	0.00219%	45,574

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.Arg207Ser
Coding: c.619C>A
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.Arg207Cys Uncertain significance ★★ ⚠ same residue
IQSEC2 p.Arg207His 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

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-arg207ser (accessed [today's date]).

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