EXT1 p.Arg741Ter
c.2221C>T · VCV4537846
Uncertain significance
Single submitter
Classification
Uncertain significance
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
Consequence
nonsense (stop-gain)
predicted LoF
gnomAD v4.1
Absent
absent from gnomAD v4.1
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Consequence | nonsense (stop-gain) | predicted loss-of-function in a haploinsufficient gene (ClinGen) |
|---|---|---|
| NMD | escapes | premature termination codon in the last exon (11 of 11) — the truncated protein is likely expressed. PVS1 input, not an applied code |
| Splicing | ||
| SpliceAI | <0.2 | no splice effect predicted · four deltas, not one · how we know |
| Pangolin | Δ0.20 | gain · loss 0.00 · SpliceAI below 0.2 · independent |
| Constraint at this position | ||
| Conservation | phyloP 8.2 | GERP 0.29, phastCons 1 |
| Overall | ||
| CADD | 41.0 | PHRED · no single calibrated threshold — expert panels disagree |
Predicted loss-of-function is descriptive, not an applied PVS1 code.
Population frequency
gnomAD v4.1 · exomes + genomes
Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.
Variant & gene context
- Gene
- EXT1
- Protein
- p.Arg741Ter
- Coding
- c.2221C>T
- MANE Select
- NM_000127
- Type
- single nucleotide variant
- Location
- chr8:117799732 (GRCh38)
- Gene constraint
- LOEUF 0.339 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 84.67 · 6 PDB
- Residue 741
- an α-helix
Similar variants
- EXT1 c.1056+1G>A Pathogenic ★★ same type
- EXT1 c.1056+1G>T Pathogenic ★★ same type
- EXT1 c.1165-1G>A Pathogenic ★★ same type
- EXT1 c.1285-1G>C Pathogenic ★★ same type
- EXT1 c.1417+1G>A Pathogenic ★★ same type
- EXT1 c.1417+1G>T Pathogenic ★★ same type
- EXT1 c.1418-1G>A Pathogenic ★★ same type
- EXT1 c.1418-2A>G Pathogenic ★★ 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/ext1-p-arg741ter (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown