Is IQSEC2 p.Pro987Ser (c.2959C>T) pathogenic?

IQSEC2 p.Pro987Ser (c.2959C>T) is classified Uncertain significance in IQSEC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-20). AlphaMissense: ambiguous (0.453); Very rare (popmax 0.000223%, nfe); Associated with intellectual disability, X-linked 1.

What condition is associated with IQSEC2 p.Pro987Ser (c.2959C>T)?

IQSEC2 p.Pro987Ser (c.2959C>T) is associated with intellectual disability, X-linked 1 (ClinVar).

How common is IQSEC2 p.Pro987Ser (c.2959C>T) in the general population?

IQSEC2 p.Pro987Ser (c.2959C>T) is very rare (popmax 0.000223%, nfe) (gnomAD).

What do computational predictors say about IQSEC2 p.Pro987Ser (c.2959C>T)?

AlphaMissense predicts ambiguous (score 0.453) — an in-silico prediction, not a clinical call.

IQSEC2 p.Pro987Ser

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.2959C>T · VCV3612094

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.453 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000223%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

intellectual disability, X-linked 1

Computational evidence

Protein change
AlphaMissense	0.453	ambiguous
REVEL	0.184	benign-leaning
SaProt	LLR -9.85	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.3, phastCons 1
Regional constraint	o/e 0.53	unconstrained · MANE · 13 kb · p 4.6e-24 · regional, not allelic
Overall
CADD	26.7	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 0.000223% European (non-Finnish) · 2/895,240 alleles

Filtering AF 3.7e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.4e-05%

Overall 0.000165% 2/1,211,285 alleles · very rare exomes 2/1,097,588 · genomes 0/113,697 · 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.Pro987Ser
Coding: c.2959C>T
MANE Select: NM_001111125
Type: single nucleotide variant
Location: chrX:53241840 (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.Pro987= Likely 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
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-pro987ser (accessed [today's date]).

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