# NM_017871.6(INTS11):c.691C>T (p.Arg231Cys)

https://sugi.bio/variant/ints11-p-arg231cys

## Summary

**INTS11 p.Arg231Cys (c.691C>T)** is classified **Uncertain significance** in INTS11 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-20). AlphaMissense: likely benign (0.1771); Very rare (popmax 0.00223%, eas); Associated with neurodevelopmental disorder with motor and language delay, ocular defects, and brain abnormalities.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs1642478934 · 2 submitters · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.00223%, eas)

## For patients & families {#patients}

This is a change in the INTS11 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, 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.Arg231Cys |
| Coding change (HGVS c.) | c.691C>T |
| MANE Select transcript | [NM_017871](https://www.ncbi.nlm.nih.gov/nuccore/NM_017871) |
| dbSNP | [rs1642478934](https://www.ncbi.nlm.nih.gov/snp/rs1642478934/) |
| Variant type | single nucleotide variant |
| Location | chr1:1314835-1314835 (GRCh38) |
| ClinVar | [VCV3065624](https://www.ncbi.nlm.nih.gov/clinvar/variation/3065624/) |

**All HGVS expressions:** `NC_000001.10:g.1250215G>A`, `NC_000001.11:g.1314835G>A`, `NM_001256456.2:c.709C>T`, `NM_001256460.2:c.604C>T`, `NM_001256462.2:c.397C>T`, `NM_001256463.2:c.388C>T`, `NM_017871.4:c.691C>T`, `NM_017871.6:c.691C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1771)
- REVEL 0.357 (indeterminate)
- SaProt LLR -10.487 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate
- Conservation: phyloP 9.52, GERP 2.14, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 28.6**. 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 1.06** across the covering region of the MANE Select transcript (1,311,862–1,324,608), spanning 12,746 bp. Chi-square p 0.087. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>C, Δ0.24 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00223%** (eas) · FAF95 6.8e-05% · FAF99 1.9e-05% · 1/44,812 in the highest group · 4/1,611,244 alleles overall — very rare (popmax 0.00223%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.00223% | 44,812 |
| European (non-Finnish) | 0.000255% | 392,887 |

*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}


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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-02-20.

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

**Submission history:** 2 submissions (2024–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-03-29 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-02-20 |

## 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, not specified, AllHighlyPenetrant.

## 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.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), [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 2026-10-15); 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 3065624). 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.*