# NM_017871.6(INTS11):c.127C>T (p.Arg43Ter)

https://sugi.bio/variant/ints11-p-arg43ter

## Summary

**INTS11 p.Arg43Ter (c.127C>T)** is classified **Pathogenic** in INTS11 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-04-13). Ultra-rare (popmax 0.0165%, mid); Associated with neurodevelopmental disorder with motor and language delay, ocular defects, and brain abnormalities.

**At a glance:** Pathogenic · review: Single submitter · 1 submitter · 1 linked condition · ultra-rare (popmax 0.0165%, mid)

## For patients & families {#patients}

This is a change in the INTS11 gene that is reported as disease-causing, but on limited review, 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.Arg43Ter |
| Coding change (HGVS c.) | c.127C>T |
| MANE Select transcript | [NM_017871](https://www.ncbi.nlm.nih.gov/nuccore/NM_017871) |
| Variant type | single nucleotide variant |
| Location | chr1:1320529-1320529 (GRCh38) |
| ClinVar | [VCV4850530](https://www.ncbi.nlm.nih.gov/clinvar/variation/4850530/) |

**All HGVS expressions:** `NC_000001.10:g.1255909G>A`, `NC_000001.11:g.1320529G>A`, `NM_001256456.2:c.145C>T`, `NM_001256460.2:c.40C>T`, `NM_001256462.2:c.139+2648C>T`, `NM_001256463.2:c.126+467C>T`, `NM_017871.6:c.127C>T`

## Computational & population evidence {#evidence}

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

- **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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor gain** (Δ 0.24) — consistent with the pathogenic call
- Conservation: phyloP 1.556, GERP -2.16, phastCons 1 — weakly conserved position
- Molecular consequence: **nonsense (stop-gain)** — 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 3 of 17**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 36.0**. 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.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.24**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.24**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.0165%** (mid) · FAF95 0.000953% · FAF99 0.000787% · 1/6,078 in the highest group · 21/1,613,708 alleles overall — ultra-rare (popmax 0.0165%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0165% | 6,078 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,472 |
| European (non-Finnish) | 0.00153% | 65,550 |
| African / African-American | 0.00133% | 74,924 |

*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 **43** lies in a β-strand.

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}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2026-04-13.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India | Pathogenic | criteria provided, single submitter | research | 2026-04-13 |

## 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.

## Similar variants {#similar}

Related INTS11 variant pages (same residue, condition, or type): [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.Glu554Gly](/variant/ints11-p-glu554gly), [INTS11 p.Gly455Ser](/variant/ints11-p-gly455ser), [INTS11 p.Gly55Ser](/variant/ints11-p-gly55ser).

### 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 4850530). 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.*