# NM_019892.6(INPP5E):c.266A>G (p.Lys89Arg)

https://sugi.bio/variant/inpp5e-p-lys89arg

## Summary

**INPP5E p.Lys89Arg (c.266A>G)** is classified **Uncertain significance** in INPP5E (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-01-15). AlphaMissense: likely benign (0.0639); Very rare (popmax 0.0027%, afr); Associated with MORM syndrome.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs909863600 · 2 submitters · 3 linked conditions · AlphaMissense likely benign · very rare (popmax 0.0027%, afr)

## For patients & families {#patients}

This is a change in the INPP5E gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, and is linked to MORM 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) | Autosomal recessive |
| Age of onset (of this condition) | Antenatal, Infancy, Neonatal |
| Diagnostic panels | INPP5E is a diagnostic-grade gene on 10 Genomics England panels |

**Commonly reported features of MORM syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Micropenis — Very frequent (99-80%)
- Visual impairment — Very frequent (99-80%)
- Delayed speech and language development — Very frequent (99-80%)
- Truncal obesity — Very frequent (99-80%)
- Cataract — Frequent (79-30%)
- Retinal dystrophy — Frequent (79-30%)
- Aggressive behavior — Frequent (79-30%)
- Hyperactivity — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0010121/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [INPP5E](https://sugi.bio/atlas/gene/INPP5E/) |
| Protein change (HGVS p.) | p.Lys89Arg |
| Coding change (HGVS c.) | c.266A>G |
| MANE Select transcript | [NM_019892](https://www.ncbi.nlm.nih.gov/nuccore/NM_019892) |
| dbSNP | [rs909863600](https://www.ncbi.nlm.nih.gov/snp/rs909863600/) |
| Variant type | single nucleotide variant |
| Location | chr9:136439154-136439154 (GRCh38) |
| ClinVar | [VCV1420868](https://www.ncbi.nlm.nih.gov/clinvar/variation/1420868/) |

**All HGVS expressions:** `NC_000009.11:g.139333606T>C`, `NC_000009.12:g.136439154T>C`, `NG_016126.1:g.5651A>G`, `NM_001318502.2:c.266A>G`, `NM_019892.6:c.266A>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0639)
- REVEL 0.055 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -4.775 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 0.487, GERP -1.96, phastCons 0.878 — weakly conserved position
- CADD: **PHRED 14.34**. 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 (gnomAD v4.1): grpmax **0.0027%** (afr) · FAF95 0.000447% · FAF99 0.000168% · 2/74,182 in the highest group · 6/1,574,314 alleles overall — very rare (popmax 0.0027%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.00327% | 30,600 |
| African / African-American (grpmax) | 0.0027% | 37,091 |
| European (non-Finnish) | 0.000172% | 582,567 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**INPP5E** population constraint: ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, 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):

- **mitochondrial disease** — Definitive (AR)
- **MORM syndrome** — Moderate (AR)
- **Joubert syndrome 1** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 88.46, 77% of residues very-high.

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

*Describes the biological roles of INPP5E (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.*


### Pathways affected {#pathways}

INPP5E participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Mitochondrial protein degradation](https://reactome.org/content/detail/R-HSA-9837999) | curated |
| [Processing of SMDT1](https://reactome.org/content/detail/R-HSA-8949664) | curated |
| [Mitochondrial protein import](https://reactome.org/content/detail/R-HSA-1268020) | electronic |

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

**Biological process:** protein processing.

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-01-15.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2023–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-01-15 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-09-05 |

## Associated conditions {#conditions}

[MORM syndrome](https://sugi.bio/atlas/disease/morm-syndrome/), [Joubert syndrome 1](https://sugi.bio/atlas/disease/joubert-syndrome-1/), [Joubert syndrome](https://sugi.bio/atlas/disease/joubert-syndrome/).

**Reported phenotype names (ClinVar):** MORM syndrome, Joubert syndrome, Joubert syndrome 1, Cerebellooculorenal syndrome 1, CEREBELLOPARENCHYMAL DISORDER IV, Familial aplasia of the vermis, JOUBERT-BOLTSHAUSER SYNDROME.

## Similar variants {#similar}

Related INPP5E variant pages (same residue, condition, or type): [PMPCA p.Thr89Ile](/variant/pmpca-p-thr89ile), [INPP5E p.Lys89=](/variant/inpp5e-p-lys89), [INPP5E p.Arg378Cys](/variant/inpp5e-p-arg378cys), [INPP5E p.Arg435Gln](/variant/inpp5e-p-arg435gln), [INPP5E p.Arg435Trp](/variant/inpp5e-p-arg435trp), [INPP5E p.Arg557His](/variant/inpp5e-p-arg557his), [INPP5E p.Arg563His](/variant/inpp5e-p-arg563his), [INPP5E p.Arg585Cys](/variant/inpp5e-p-arg585cys).

### 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 1420868). 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.*