TMIE p.Pro41=
c.123G>A · rs765221463 · VCV517406
Likely benign
Multiple submitters
Classification
Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 3 submitters
gnomAD v4.1
Rare
ultra-rare (popmax 0.0198%, sas)
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Splicing | ||
| SpliceAI | <0.2 | no splice effect predicted · four deltas, not one · how we know |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP -6.6 | GERP -3.5 |
| Overall | ||
| CADD | 7.31 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.0198%
South Asian · 18/91,084 alleles
Filtering AF
0.0127%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.0115%
Overall
0.0129%
209/1,614,028 alleles · ultra-rare
exomes 197/1,461,746 · genomes 12/152,282 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| South Asiangrpmax | 0.0198% | 5,060 |
| Remaining individualsnot grpmax-eligible | 0.0192% | 5,209 |
| Admixed American | 0.0183% | 5,457 |
| Middle Eastern | 0.0165% | 6,060 |
| European (non-Finnish) | 0.0139% | 7,195 |
| African / African-American | 0.004% | 25,012 |
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
- TMIE
- Protein
- p.Pro41=
- Coding
- c.123G>A
- MANE Select
- NM_147196
- dbSNP
- rs765221463
- Type
- single nucleotide variant
- Location
- chr3:46705819 (GRCh38)
- Gene constraint
- LOEUF 1.475 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 63.41
Similar variants
- TMIE p.Pro41Leu Uncertain significance ★★ same residue
- TMIE p.Pro41fs Pathogenic same residue
- TMIE p.Arg84Trp Likely pathogenic ★★ same type
- TMIE p.Glu31Gly Pathogenic/Likely pathogenic ★★ ⚠ same type
- TMIE c.-154G>A Uncertain significance ★★ same type
- TMIE c.*253G>A Uncertain significance ★★ same type
- TMIE p.Ala17Thr Uncertain significance ★★ ⚠ same type
- TMIE p.Ala2Gly 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/tmie-p-pro41 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown