# NM_001111125.3(IQSEC2):c.48A>T (p.Pro16=)

https://sugi.bio/variant/iqsec2-p-pro16

## Summary

**IQSEC2 p.Pro16= (c.48A>T)** is classified **Likely benign** in IQSEC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-24). Absent from gnomAD v4.1; Associated with intellectual disability, X-linked 1.

**At a glance:** Likely benign · review: Single submitter · 1 submitter · 1 linked condition · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the IQSEC2 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to intellectual disability, X-linked 1.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | X-linked recessive |
| Age of onset (of this condition) | Infancy, Neonatal |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | IQSEC2 is a diagnostic-grade gene on 7 Genomics England panels |

**Commonly reported features of Severe intellectual disability-progressive postnatal microcephaly-midline stereotypic hand movements syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Progressive microcephaly — Frequent (79-30%)
- Atypical behavior — Frequent (79-30%)
- Seizure — Frequent (79-30%)
- Hypotonia — Frequent (79-30%)
- Global developmental delay — Frequent (79-30%)
- Developmental regression — Frequent (79-30%)
- Intellectual disability, severe — Frequent (79-30%)
- Stereotypical hand wringing — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0022699/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [IQSEC2](https://sugi.bio/atlas/gene/IQSEC2/) |
| Protein change (HGVS p.) | p.Pro16= |
| Coding change (HGVS c.) | c.48A>T |
| MANE Select transcript | [NM_001111125](https://www.ncbi.nlm.nih.gov/nuccore/NM_001111125) |
| Variant type | single nucleotide variant |
| Location | chrX:53321076-53321076 (GRCh38) |
| ClinVar | [VCV4742559](https://www.ncbi.nlm.nih.gov/clinvar/variation/4742559/) |

**All HGVS expressions:** `LRG_1194:g.5275A>T`, `LRG_1194t1:c.48A>T`, `NC_000023.10:g.53350274T>A`, `NC_000023.11:g.53321076T>A`, `NG_021296.2:g.5275A>T`, `NM_001111125.3:c.48A>T`, `NM_001410736.1:c.48A>T`, `NM_001441092.1:c.48A>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 2.827, GERP -3.51, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 13.03**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**IQSEC2** population constraint: ClinGen dosage — haploinsufficiency 3/3, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **X-linked complex neurodevelopmental disorder** — Definitive (XL)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 54.46, 22% of residues very-high.

**2 experimental structure(s)** (PDB): [6FAE](https://www.rcsb.org/structure/6FAE), [9M46](https://www.rcsb.org/structure/9M46).

## What this gene does {#gene-function}

*Describes the biological roles of IQSEC2 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** IQSEC2's established molecular role includes guanyl-nucleotide exchange factor activity.


### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** guanyl-nucleotide exchange factor activity.

**Biological process:** modulation of chemical synaptic transmission, regulation of neurotransmitter receptor localization to postsynaptic specialization membrane.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2026-01-24.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-24 |

## Associated conditions {#conditions}

[intellectual disability, X-linked 1](https://sugi.bio/atlas/disease/intellectual-disability-x-linked-1/).

**Reported phenotype names (ClinVar):** Intellectual disability, X-linked 1, Atkin Flaitz Patil Smith syndrome, MENTAL RETARDATION, X-LINKED 18, MENTAL RETARDATION, X-LINKED 78, INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED 1.

## Similar variants {#similar}

Related IQSEC2 variant pages (same residue, condition, or type): [IQSEC2 c.2459+21C>T](/variant/iqsec2-c-2459-plus-21c-t), [IQSEC2 c.2889+1G>A](/variant/iqsec2-c-2889-plus-1g-a), [IQSEC2 p.Ala836Val](/variant/iqsec2-p-ala836val), [IQSEC2 p.Arg1055Ter](/variant/iqsec2-p-arg1055ter), [IQSEC2 p.Arg1145Ter](/variant/iqsec2-p-arg1145ter), [IQSEC2 p.Arg531Ter](/variant/iqsec2-p-arg531ter), [IQSEC2 p.Arg758Ter](/variant/iqsec2-p-arg758ter), [IQSEC2 p.Arg855Ter](/variant/iqsec2-p-arg855ter).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 4742559). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*