# NM_017871.6(INTS11):c.1652_1653del (p.Val551fs)

https://sugi.bio/variant/ints11-p-val551fs

## Summary

**INTS11 p.Val551fs (c.1652_1653del)** is classified **Likely pathogenic** in INTS11 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-04-17). Very rare (popmax 0.00115%, sas); Associated with neurodevelopmental disorder with motor and language delay, ocular defects, and brain abnormalities.

**At a glance:** Likely pathogenic · review: No assertion criteria · 1 submitter · 1 linked condition · very rare (popmax 0.00115%, sas)

## For patients & families {#patients}

This is a change in the INTS11 gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to neurodevelopmental disorder with motor and language delay, ocular defects, and brain abnormalities.

*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 | [INTS11](https://sugi.bio/atlas/gene/INTS11/) |
| Protein change (HGVS p.) | p.Val551fs |
| Coding change (HGVS c.) | c.1652_1653del |
| MANE Select transcript | [NM_017871](https://www.ncbi.nlm.nih.gov/nuccore/NM_017871) |
| Variant type | Microsatellite |
| Location | chr1:1312102-1312103 (GRCh38) |
| ClinVar | [VCV3359221](https://www.ncbi.nlm.nih.gov/clinvar/variation/3359221/) |

**All HGVS expressions:** `NC_000001.10:g.1247482CA[1]`, `NC_000001.11:g.1312102CA[1]`, `NM_001256456.2:c.1670_1671del`, `NM_001256460.2:c.1565_1566del`, `NM_001256462.2:c.1358_1359del`, `NM_001256463.2:c.1349_1350del`, `NM_017871.6:c.1652_1653del`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 6.013, GERP 1.86, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.223, pLI 6.2511e-27. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 16 of 17**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no microsatellite variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00115%** (sas) · FAF95 6.9e-05% · FAF99 1.9e-05% · 1/86,848 in the highest group · 5/1,576,126 alleles overall — very rare (popmax 0.00115%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.00164% | 61,064 |
| South Asian (grpmax) | 0.00115% | 86,848 |
| European (non-Finnish) | 0.000259% | 386,716 |

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}

**INTS11** population constraint: LOEUF 1.223, pLI 6.2511e-27, missense-Z -0.90214. *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 **551** lies in a β-strand; a UniProt-annotated variant site (in nedmlob; uncertain significance).

AlphaFold model confidence (whole protein): pLDDT 90.82, 67% 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 INTS11 (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:** INTS11's established molecular role includes RNA endonuclease activity.


### Pathways affected {#pathways}

INTS11 participates in **1 Reactome pathway** (⚕ = disease pathway):

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

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

**Molecular function:** RNA endonuclease activity.

**Biological process:** snRNA processing, regulation of transcription elongation by RNA polymerase II, snRNA 3'-end processing, RNA polymerase II transcription initiation surveillance.

## Clinical significance {#significance}

**Likely pathogenic** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2024-04-17.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Undiagnosed Diseases Network, NIH | Likely pathogenic | no assertion criteria provided | clinical testing | 2024-04-17 |

## Associated conditions {#conditions}

[neurodevelopmental disorder with motor and language delay, ocular defects, and brain abnormalities](https://sugi.bio/atlas/disease/neurodevelopmental-disorder-with-motor-and-language-delay-ocular-defects-and-brain-abnormalities/).

**Reported phenotype names (ClinVar):** Neurodevelopmental disorder with motor and language delay, ocular defects, and brain abnormalities.

## Same-residue context {#hotspot}

Residue **551** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [INTS11 p.Val551Glu](/variant/ints11-p-val551glu). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related INTS11 variant pages (same residue, condition, or type): [INTS11 p.Val551Glu](/variant/ints11-p-val551glu), [INTS11 p.Arg521fs](/variant/ints11-p-arg521fs), [INTS11 c.28+1406C>T](/variant/ints11-c-28-plus-1406c-t), [INTS11 p.Arg231Cys](/variant/ints11-p-arg231cys), [INTS11 p.Glu227Lys](/variant/ints11-p-glu227lys), [INTS11 c.1738-1G>A](/variant/ints11-c-1738-minus-1g-a), [INTS11 p.Arg17Leu](/variant/ints11-p-arg17leu), [INTS11 p.Arg43Ter](/variant/ints11-p-arg43ter).

### 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 3359221). 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.*