# NM_001351695.2(INTS2):c.1199C>A (p.Ala400Asp)

https://sugi.bio/variant/ints2-p-ala400asp

## Summary

**INTS2 p.Ala400Asp (c.1199C>A)** is classified **Uncertain significance** in INTS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-10). AlphaMissense: likely pathogenic (0.9206); Ultra-rare (popmax 0.016%, afr).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely pathogenic · ultra-rare (popmax 0.016%, afr)

## For patients & families {#patients}

This is a change in the INTS2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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 | [INTS2](https://sugi.bio/atlas/gene/INTS2/) |
| Protein change (HGVS p.) | p.Ala400Asp |
| Coding change (HGVS c.) | c.1199C>A |
| MANE Select transcript | [NM_001351695](https://www.ncbi.nlm.nih.gov/nuccore/NM_001351695) |
| Variant type | single nucleotide variant |
| Location | chr17:61904568-61904568 (GRCh38) |
| ClinVar | [VCV4039016](https://www.ncbi.nlm.nih.gov/clinvar/variation/4039016/) |

**All HGVS expressions:** `NC_000017.10:g.59981929G>T`, `NC_000017.11:g.61904568G>T`, `NG_196541.1:g.352G>T`, `NM_001330417.2:c.1199C>A`, `NM_001351695.2:c.1199C>A`, `NM_020748.4:c.1223C>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9206)
- REVEL 0.326 (indeterminate)
- SaProt LLR -9.156 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate
- Conservation: phyloP 8.545, GERP 1.45, phastCons 1 — highly conserved (agrees)
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **A408D** vs ClinVar **A400D**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- CADD: **PHRED 25.7**. 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 0.84** across the covering region of the MANE Select transcript (61,867,560–61,926,402), spanning 58,842 bp. Chi-square p 6.2e-09. 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, Δ0.20 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 **0.016%** (afr) · FAF95 0.00923% · FAF99 0.00723% · 12/74,814 in the highest group · 25/1,611,116 alleles overall — ultra-rare (popmax 0.016%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.016% | 6,234 |
| Remaining individuals (not grpmax-eligible) | 0.00321% | 31,194 |
| European (non-Finnish) | 0.000933% | 107,168 |

*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}

**INTS2** population constraint: LOEUF 0.491, pLI 0.98274, missense-Z 2.2139. *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 78.90, 27% 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 INTS2 (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}

INTS2 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 2025-06-10.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-06-10 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related INTS2 variant pages (same residue, condition, or type): [INTS2 c.-17A>G](/variant/ints2-c-minus-17a-g), [INTS2 c.-1A>G](/variant/ints2-c-minus-1a-g), [INTS2 c.-3A>G](/variant/ints2-c-minus-3a-g), [INTS2 p.Ala1125Ser](/variant/ints2-p-ala1125ser), [INTS2 p.Ala379Val](/variant/ints2-p-ala379val), [INTS2 p.Ala57Val](/variant/ints2-p-ala57val), [INTS2 p.Ala599Val](/variant/ints2-p-ala599val), [INTS2 p.Ala662Gly](/variant/ints2-p-ala662gly).

### 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 4039016). 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.*