INTS1 c.546+4T>C
Likely benign
Single submitter
Classification
Likely benign
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
low-frequency (popmax 1.39%, afr)
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Splicing | ||
| Splice region | donor +4 | donor splice region (+4, within the first 6 intronic nt) · inside the BP7-excluded zone |
|---|---|---|
| SpliceAI | <0.2 | all four deltas below 0.2 · A>C here scores Δ0.22 · evaluated, not missing |
| Constraint at this position | ||
| Conservation | phyloP -2.5 | GERP -1.7 |
| Non-coding constraint | Z 2.33 | 1 kb window · o/e 0.83 · regional · uncalibrated |
| Overall | ||
| CADD | 11.99 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
1.39%
African / African-American · 1,039/74,546 alleles
Filtering AF
1.32%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 1.3%
Overall
0.0725%
1,149/1,584,614 alleles · low-frequency
exomes 568/1,432,326 · genomes 581/152,288 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| African / African-Americangrpmax | 1.39% | 72 |
| Remaining individualsnot grpmax-eligible | 0.0589% | 1,698 |
| Admixed American | 0.0574% | 1,744 |
| Middle Eastern | 0.0333% | 3,001 |
| European (non-Finnish) | 0.00328% | 30,529 |
| South Asian | 0.00113% | 88,826 |
Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.
Variant & gene context
- Gene
- INTS1
- Coding
- c.546+4T>C
- MANE Select
- NM_001080453
- Type
- single nucleotide variant
- Location
- chr7:1500166 (GRCh38)
- Gene constraint
- LOEUF 0.785 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 75.49 · 8 PDB
Similar variants
- INTS1 c.3430-2A>C Likely pathogenic ★★ same type
- INTS1 p.Arg101Ter Likely pathogenic ★★ same type
- INTS1 p.Glu182Ter Likely pathogenic ★★ same type
- INTS1 c.1283+5G>A Uncertain significance ★★ same type
- INTS1 c.2977-5C>T Uncertain significance ★★ same type
- INTS1 p.Ala1112Val Uncertain significance ★★ ⚠ same type
- INTS1 p.Ala1505Val Uncertain significance ★★ ⚠ same type
- INTS1 p.Ala1854Val Uncertain significance ★★ ⚠ same type
Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →
Cite Sugi Variant
Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/ints1-c-546-plus-4t-c (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown