# NM_012141.3(INTS6):c.90C>T (p.Gly30=)

https://sugi.bio/variant/ints6-p-gly30

## Summary

**INTS6 p.Gly30= (c.90C>T)** is classified **Uncertain significance** in INTS6 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-06-21). Absent from gnomAD v4.1; Associated with INTS6-related disorder.

**At a glance:** Uncertain significance · review: No assertion criteria · 1 submitter · 1 linked condition · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the INTS6 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to INTS6-related disorder.

*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 | [INTS6](https://sugi.bio/atlas/gene/INTS6/) |
| Protein change (HGVS p.) | p.Gly30= |
| Coding change (HGVS c.) | c.90C>T |
| MANE Select transcript | [NM_012141](https://www.ncbi.nlm.nih.gov/nuccore/NM_012141) |
| Variant type | single nucleotide variant |
| Location | chr13:51452436-51452436 (GRCh38) |
| ClinVar | [VCV3346030](https://www.ncbi.nlm.nih.gov/clinvar/variation/3346030/) |

**All HGVS expressions:** `NC_000013.10:g.52026572G>A`, `NC_000013.11:g.51452436G>A`, `NG_187717.1:g.345G>A`, `NM_001039937.2:c.51C>T`, `NM_001039938.2:c.90C>T`, `NM_001306091.2:c.-729C>T`, `NM_012141.3:c.90C>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 **donor gain** (Δ 0.95) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 11.367, GERP 0.336, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 24.3**. 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 **0.01**, acceptor gain **0.00**, donor gain **0.95**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.95**.
- Pangolin: Δ**0.55** (gain), gain 0.55 / loss 0.05. 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**INTS6** population constraint: LOEUF 0.23, pLI 1, missense-Z 4.672. *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 **30** lies in the vwfa domain; an α-helix.

AlphaFold model confidence (whole protein): pLDDT 72.80, 40% of residues very-high.

**9 experimental structure(s)** (PDB): [7BV7](https://www.rcsb.org/structure/7BV7), [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).

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

*Describes the biological roles of INTS6 (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:** INTS6's established molecular role includes protein-macromolecule adaptor activity. p.Gly30= falls in the vwfa domain.


### Pathways affected {#pathways}

INTS6 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:** protein-macromolecule adaptor activity.

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

## Clinical significance {#significance}

**Uncertain significance** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2024-06-21.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Uncertain significance | no assertion criteria provided | clinical testing | 2024-06-21 |

## Associated conditions {#conditions}

[INTS6-related disorder](https://sugi.bio/atlas/disease/ints6-related-disorder/).

**Reported phenotype names (ClinVar):** INTS6-related disorder, INTS6-related condition.

## Similar variants {#similar}

Related INTS6 variant pages (same residue, condition, or type): [INTS6 p.Gly30Val](/variant/ints6-p-gly30val), [SERPINE3 p.Lys30Arg](/variant/serpine3-p-lys30arg), [INTS6 p.Gln228Glu](/variant/ints6-p-gln228glu), [INTS6 p.Val381Gly](/variant/ints6-p-val381gly), [INTS6 c.1275+1G>A](/variant/ints6-c-1275-plus-1g-a), [INTS6 p.Arg550Ter](/variant/ints6-p-arg550ter), [INTS6 c.340-3T>C](/variant/ints6-c-340-minus-3t-c), [INTS6 p.Ala738Gly](/variant/ints6-p-ala738gly).

### 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 3346030). 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.*