Is IQSEC2 p.Pro8Ser (c.22C>T) pathogenic?

IQSEC2 p.Pro8Ser (c.22C>T) is classified Uncertain significance in IQSEC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-18). AlphaMissense: likely benign (0.0642); Very rare (popmax 0.00381%, sas); Associated with intellectual disability, X-linked 1.

What condition is associated with IQSEC2 p.Pro8Ser (c.22C>T)?

IQSEC2 p.Pro8Ser (c.22C>T) is associated with intellectual disability, X-linked 1 (ClinVar).

How common is IQSEC2 p.Pro8Ser (c.22C>T) in the general population?

IQSEC2 p.Pro8Ser (c.22C>T) is very rare (popmax 0.00381%, sas) (gnomAD).

What do computational predictors say about IQSEC2 p.Pro8Ser (c.22C>T)?

AlphaMissense predicts likely benign (score 0.0642) — an in-silico prediction, not a clinical call.

IQSEC2 p.Pro8Ser

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.22C>T · VCV3688021

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0642 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00381%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

intellectual disability, X-linked 1

Computational evidence

Protein change
AlphaMissense	0.0642	likely benign
REVEL	0.079	moderately benign-leaning
SaProt	LLR -7.18	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8	GERP 0.72, phastCons 1
Regional constraint	o/e 0.62	unconstrained · MANE · 683 bp · p 3.4e-08 · regional, not allelic
Overall
CADD	24.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00381% South Asian · 2/52,446 alleles

Filtering AF 0.000632% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000237%

Overall 0.000174% 2/1,148,680 alleles · very rare exomes 2/1,036,685 · genomes 0/111,995 · 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.Pro8Ser
Coding: c.22C>T
MANE Select: NM_001111125
Type: single nucleotide variant
Location: chrX:53321102 (GRCh38)
Structure: AlphaFold pLDDT 54.46 · 2 PDB

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.Pro8Arg Uncertain significance ★★ ⚠ same residue
IQSEC2 p.Pro8= Likely benign ★★ same residue
IQSEC2 p.Pro8fs Pathogenic ★ 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-pro8ser (accessed [today's date]).

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