# NM_002547.3(OPHN1):c.2345T>G (p.Phe782Cys)

https://sugi.bio/variant/ophn1-p-phe782cys

## Summary

**OPHN1 p.Phe782Cys (c.2345T>G)** is classified **Uncertain significance** in OPHN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-14). AlphaMissense: likely pathogenic (0.9168); Very rare (popmax 0.000336%, nfe); Associated with X-linked intellectual disability-cerebellar hypoplasia syndrome.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 0.000336%, nfe)

## For patients & families {#patients}

This is a change in the OPHN1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to X-linked intellectual disability-cerebellar hypoplasia syndrome.

*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 dominant |
| Age of onset (of this condition) | Infancy, Neonatal |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | OPHN1 is a diagnostic-grade gene on 14 Genomics England panels |

**Commonly reported features of X-linked intellectual disability-cerebellar hypoplasia syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Intellectual disability — Very frequent (99-80%)
- Global developmental delay — Very frequent (99-80%)
- Cerebellar hypoplasia — Very frequent (99-80%)
- Reduced social responsiveness — Frequent (79-30%)
- Strabismus — Frequent (79-30%)
- Deeply set eye — Frequent (79-30%)
- Autistic behavior — Frequent (79-30%)
- Reduced eye contact — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0009947/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [OPHN1](https://sugi.bio/atlas/gene/OPHN1/) |
| Protein change (HGVS p.) | p.Phe782Cys |
| Coding change (HGVS c.) | c.2345T>G |
| MANE Select transcript | [NM_002547](https://www.ncbi.nlm.nih.gov/nuccore/NM_002547) |
| Variant type | single nucleotide variant |
| Location | chrX:68052570-68052570 (GRCh38) |
| ClinVar | [VCV4079474](https://www.ncbi.nlm.nih.gov/clinvar/variation/4079474/) |

**All HGVS expressions:** `NC_000023.10:g.67272412A>C`, `NC_000023.11:g.68052570A>C`, `NG_008960.1:g.385888T>G`, `NM_001437258.1:c.2021T>G`, `NM_002547.3:c.2345T>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9168)
- REVEL 0.217 (benign-leaning) — differs from AlphaMissense
- SaProt LLR -8.99 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense calls this damaging; REVEL and SaProt do not
- Conservation: phyloP 11.073, GERP 1.31, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 26.8**. 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.*
- Regional missense constraint: **o/e 1.15** across the covering region of the MANE Select transcript (68,048,427–68,073,176), spanning 24,749 bp. Chi-square p 0.063. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code 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 (gnomAD v4.1): grpmax **0.000336%** (nfe) · FAF95 8.9e-05% · FAF99 2.5e-05% · 3/893,768 in the highest group · 3/1,208,391 alleles overall — very rare (popmax 0.000336%, nfe).

*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}

**OPHN1** 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 intellectual disability-cerebellar hypoplasia syndrome** — Definitive (XL)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 74.86, 51% of residues very-high.

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

*Describes the biological roles of OPHN1 (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:** OPHN1's established molecular role includes phospholipid binding.


### Pathways affected {#pathways}

OPHN1 participates in **10 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [CDC42 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013148) | curated |
| [RAC1 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013149) | curated |
| [RAC2 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013404) | curated |
| [RAC3 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013423) | curated |
| [RHOA GTPase cycle](https://reactome.org/content/detail/R-HSA-8980692) | curated |
| [RHOB GTPase cycle](https://reactome.org/content/detail/R-HSA-9013026) | curated |
| [RHOC GTPase cycle](https://reactome.org/content/detail/R-HSA-9013106) | curated |
| [RHOG GTPase cycle](https://reactome.org/content/detail/R-HSA-9013408) | curated |
| [RHOJ GTPase cycle](https://reactome.org/content/detail/R-HSA-9013409) | curated |
| [RHOQ GTPase cycle](https://reactome.org/content/detail/R-HSA-9013406) | curated |

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

**Molecular function:** phospholipid binding.

**Biological process:** cerebellar granule cell differentiation, cerebral cortex neuron differentiation, neuron differentiation, neuron projection development, cell junction assembly, regulation of Rho protein signal transduction.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-05-14.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Revvity Omics, Revvity | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-05-14 |

## Associated conditions {#conditions}

[X-linked intellectual disability-cerebellar hypoplasia syndrome](https://sugi.bio/atlas/disease/x-linked-intellectual-disability-cerebellar-hypoplasia-syndrome/).

**Reported phenotype names (ClinVar):** X-linked intellectual disability-cerebellar hypoplasia syndrome, INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED, SYNDROMIC, BILLUART TYPE, MENTAL RETARDATION, X-LINKED 60.

## Similar variants {#similar}

Related OPHN1 variant pages (same residue, condition, or type): [OPHN1 c.1138+1G>A](/variant/ophn1-c-1138-plus-1g-a), [OPHN1 c.1202-1G>A](/variant/ophn1-c-1202-minus-1g-a), [OPHN1 c.155-2A>C](/variant/ophn1-c-155-minus-2a-c), [OPHN1 p.Arg497Ter](/variant/ophn1-p-arg497ter), [OPHN1 p.Gln416Ter](/variant/ophn1-p-gln416ter), [OPHN1 p.Thr326Met](/variant/ophn1-p-thr326met), [OPHN1 p.Arg788Gln](/variant/ophn1-p-arg788gln), [OPHN1 p.Asp538Gly](/variant/ophn1-p-asp538gly).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 4079474). 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.*