# NM_018250.4(INTS9):c.781C>T (p.Leu261Phe)

https://sugi.bio/variant/ints9-p-leu261phe

## Summary

**INTS9 p.Leu261Phe (c.781C>T)** is classified **Uncertain significance** in INTS9 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-22). AlphaMissense: ambiguous (0.5197); Very rare (popmax 8.48e-05%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2487251922 · 1 submitter · AlphaMissense ambiguous · very rare (popmax 8.48e-05%, nfe)

## For patients & families {#patients}

This is a change in the INTS9 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 | [INTS9](https://sugi.bio/atlas/gene/INTS9/) |
| Protein change (HGVS p.) | p.Leu261Phe |
| Coding change (HGVS c.) | c.781C>T |
| MANE Select transcript | [NM_018250](https://www.ncbi.nlm.nih.gov/nuccore/NM_018250) |
| dbSNP | [rs2487251922](https://www.ncbi.nlm.nih.gov/snp/rs2487251922/) |
| Variant type | single nucleotide variant |
| Location | chr8:28796619-28796619 (GRCh38) |
| ClinVar | [VCV3110254](https://www.ncbi.nlm.nih.gov/clinvar/variation/3110254/) |

**All HGVS expressions:** `NC_000008.10:g.28654136G>A`, `NC_000008.11:g.28796619G>A`, `NG_016981.2:g.98563C>T`, `NM_001145159.3:c.718C>T`, `NM_001172562.2:c.709C>T`, `NM_001363038.2:c.781C>T`, `NM_018250.4:c.781C>T`, `NR_026826.3:n.677C>T`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense and REVEL are indeterminate here — the available evidence is described below.

- AlphaMissense **ambiguous** (0.5197) — no call either way
- REVEL 0.427 (indeterminate)
- SaProt LLR -12.18 (damaging)
- SpliceAI predicts **acceptor gain** (Δ 0.21) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 11.64, GERP 2.4, phastCons 1 — highly conserved
- CADD: **PHRED 33.0**. 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 0.67** across the covering region of the MANE Select transcript (28,777,918–28,796,626), spanning 18,708 bp. Chi-square p 5.8e-07. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.01**, donor loss **0.00**, acceptor gain **0.21**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.01**, donor loss **0.00**, acceptor gain **0.21**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **8.48e-05%** (nfe) · 1/1,179,816 in the highest group · 1/1,613,964 alleles overall — very rare (popmax 8.48e-05%, 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}

**INTS9** population constraint: LOEUF 0.871, pLI 3.8062e-10, missense-Z 1.6535. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **261** lies in a β-strand.

AlphaFold model confidence (whole protein): pLDDT 90.95, 76% of residues very-high.

**15 experimental structure(s)** (PDB): [5V8W](https://www.rcsb.org/structure/5V8W), [7BFP](https://www.rcsb.org/structure/7BFP), [7BFQ](https://www.rcsb.org/structure/7BFQ), [7CUN](https://www.rcsb.org/structure/7CUN), [7PKS](https://www.rcsb.org/structure/7PKS), [7YCX](https://www.rcsb.org/structure/7YCX).

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

*Describes the biological roles of INTS9 (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}

INTS9 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [RNA polymerase II transcribes snRNA genes](https://reactome.org/content/detail/R-HSA-6807505) | other |

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

**Biological process:** snRNA processing, negative regulation of transforming growth factor beta receptor signaling pathway, regulation of transcription elongation by RNA polymerase II, snRNA 3'-end processing, RNA polymerase II transcription initiation surveillance.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-12-22.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-12-22 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related INTS9 variant pages (same residue, condition, or type): [INTS9 p.Leu417Pro](/variant/ints9-p-leu417pro), [INTS9 p.Ala208Val](/variant/ints9-p-ala208val), [INTS9 p.Ala286Asp](/variant/ints9-p-ala286asp), [INTS9 p.Ala319Val](/variant/ints9-p-ala319val), [INTS9 p.Ala506Thr](/variant/ints9-p-ala506thr), [INTS9 p.Ala560Thr](/variant/ints9-p-ala560thr), [INTS9 p.Arg401Cys](/variant/ints9-p-arg401cys), [INTS9 p.Arg401His](/variant/ints9-p-arg401his).

### 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 3110254). 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.*