# NM_001080453.3(INTS1):c.2063C>T (p.Ala688Val)

https://sugi.bio/variant/ints1-p-ala688val

## Summary

**INTS1 p.Ala688Val (c.2063C>T)** is classified **Uncertain significance** in INTS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-19). AlphaMissense: likely benign (0.1932); Very rare (popmax 0.0047%, eas); Associated with neurodevelopmental disorder with cataracts, poor growth, and dysmorphic facies.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.0047%, eas)

## For patients & families {#patients}

This is a change in the INTS1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to neurodevelopmental disorder with cataracts, poor growth, and dysmorphic facies.

*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 | [INTS1](https://sugi.bio/atlas/gene/INTS1/) |
| Protein change (HGVS p.) | p.Ala688Val |
| Coding change (HGVS c.) | c.2063C>T |
| MANE Select transcript | [NM_001080453](https://www.ncbi.nlm.nih.gov/nuccore/NM_001080453) |
| Variant type | single nucleotide variant |
| Location | chr7:1493759-1493759 (GRCh38) |
| ClinVar | [VCV4056797](https://www.ncbi.nlm.nih.gov/clinvar/variation/4056797/) |

**All HGVS expressions:** `NC_000007.13:g.1533395G>A`, `NC_000007.14:g.1493759G>A`, `NG_110126.1:g.93G>A`, `NM_001080453.3:c.2063C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1932)
- REVEL 0.194 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.546 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **donor gain** (Δ 0.59) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 11.64, GERP 1.38, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 30.0**. 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 0.96** across the covering region of the MANE Select transcript (1,482,643–1,503,960), spanning 21,317 bp. Chi-square p 0.12. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.02**, acceptor gain **0.00**, donor gain **0.59**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.59**.
- Pangolin: Δ**0.33** (gain), gain 0.33 / loss 0.06. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0047%** (eas) · FAF95 0.00089% · FAF99 0.000728% · 2/42,522 in the highest group · 24/1,577,298 alleles overall — very rare (popmax 0.0047%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.0047% | 21,261 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00345% | 28,944 |
| South Asian | 0.00233% | 42,957 |
| Admixed American | 0.00183% | 54,552 |
| Remaining individuals (not grpmax-eligible) | 0.00164% | 61,162 |
| European (non-Finnish) | 0.00146% | 68,423 |

*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}

**INTS1** population constraint: LOEUF 0.785, pLI 2.0443e-30, missense-Z -1.9354. *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 75.49, 15% of residues very-high.

**8 experimental structure(s)** (PDB): [7CUN](https://www.rcsb.org/structure/7CUN), [7PKS](https://www.rcsb.org/structure/7PKS), [7YCX](https://www.rcsb.org/structure/7YCX), [8RBX](https://www.rcsb.org/structure/8RBX), [8RBZ](https://www.rcsb.org/structure/8RBZ), [8RC4](https://www.rcsb.org/structure/8RC4).

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

*Describes the biological roles of INTS1 (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}

INTS1 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}

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

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-09-19.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-09-19 |

## Associated conditions {#conditions}

[neurodevelopmental disorder with cataracts, poor growth, and dysmorphic facies](https://sugi.bio/atlas/disease/neurodevelopmental-disorder-with-cataracts-poor-growth-and-dysmorphic-facies/).

**Reported phenotype names (ClinVar):** Neurodevelopmental disorder with cataracts, poor growth, and dysmorphic facies.

## Similar variants {#similar}

Related INTS1 variant pages (same residue, condition, or type): [INTS1 c.3430-2A>C](/variant/ints1-c-3430-minus-2a-c), [INTS1 p.Arg101Ter](/variant/ints1-p-arg101ter), [INTS1 c.1283+5G>A](/variant/ints1-c-1283-plus-5g-a), [INTS1 c.2977-5C>T](/variant/ints1-c-2977-minus-5c-t), [INTS1 p.Ala745Thr](/variant/ints1-p-ala745thr), [INTS1 p.Arg1130Cys](/variant/ints1-p-arg1130cys), [INTS1 p.Arg1685Gln](/variant/ints1-p-arg1685gln), [INTS1 p.Arg1800Gln](/variant/ints1-p-arg1800gln).

### 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 4056797). 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.*