# NM_002547.3(OPHN1):c.916A>C (p.Lys306Gln)

https://sugi.bio/variant/ophn1-p-lys306gln

## Summary

**OPHN1 p.Lys306Gln (c.916A>C)** is classified **Uncertain significance** in OPHN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-11-01). AlphaMissense: likely pathogenic (0.5663); Absent from gnomAD v4.1.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2077560487 · 1 submitter · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## 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.

*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.*

**Support & next steps:** [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.Lys306Gln |
| Coding change (HGVS c.) | c.916A>C |
| MANE Select transcript | [NM_002547](https://www.ncbi.nlm.nih.gov/nuccore/NM_002547) |
| dbSNP | [rs2077560487](https://www.ncbi.nlm.nih.gov/snp/rs2077560487/) |
| Variant type | single nucleotide variant |
| Location | chrX:68206590-68206590 (GRCh38) |
| ClinVar | [VCV872372](https://www.ncbi.nlm.nih.gov/clinvar/variation/872372/) |

**All HGVS expressions:** `NC_000023.10:g.67426432T>G`, `NC_000023.11:g.68206590T>G`, `NG_008960.1:g.231868A>C`, `NM_002547.3:c.916A>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.5663)
- REVEL 0.214 (benign-leaning) — differs from AlphaMissense
- SaProt LLR -10.021 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt call this damaging; REVEL does not
- Conservation: phyloP 7.786, GERP 2.1, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 26.1**. 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 0.60** across the covering region of the MANE Select transcript (68,073,177–68,210,272), spanning 137,095 bp. Chi-square p 1.6e-11. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. This allele is not in the release, so all four of its deltas are under 0.2. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, and here that is proven rather than inferred: a different substitution at this very position, T>A, IS in the release and scores Δ0.42 donor loss, so SpliceAI evaluated this position and this allele was not among the ones that cleared the filter. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- 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}

**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}

Residue **306** lies in the ph domain.

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. p.Lys306Gln falls in the ph domain.


### 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 2019-11-01.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| CeGaT Center for Human Genetics Tuebingen | Uncertain significance | criteria provided, single submitter | clinical testing | 2019-11-01 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## 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.Arg243Trp](/variant/ophn1-p-arg243trp), [OPHN1 p.Arg497Ter](/variant/ophn1-p-arg497ter), [OPHN1 p.Arg597Ter](/variant/ophn1-p-arg597ter), [OPHN1 p.Gln416Ter](/variant/ophn1-p-gln416ter), [OPHN1 p.Thr326Met](/variant/ophn1-p-thr326met).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 872372). 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.*