TMEM67 p.Pro93=
c.279T>C · rs199900812 · VCV698786
Likely benign
Multiple submitters
Classification
Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 2 submitters
gnomAD v4.1
Rare
ultra-rare (popmax 0.0254%, amr)
Conditions
2
Meckel syndrome
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| REVEL | 0.037 | moderately benign-leaning |
|---|---|---|
| Splicing | ||
| SpliceAI | <0.2 | no splice effect predicted · four deltas, not one · how we know |
| Constraint at this position | ||
| Conservation | phyloP 0.18 | GERP -0.59, phastCons 0.002 |
| Overall | ||
| CADD | 4.764 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.0254%
Admixed American · 15/59,162 alleles
Filtering AF
0.0156%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.0126%
Overall
0.00126%
20/1,592,332 alleles · ultra-rare
exomes 12/1,441,872 · genomes 8/150,460 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Admixed Americangrpmax | 0.0254% | 3,944 |
| Remaining individualsnot grpmax-eligible | 0.0065% | 15,392 |
| African / African-American | 0.00135% | 74,004 |
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
- TMEM67
- Protein
- p.Pro93=
- Coding
- c.279T>C
- MANE Select
- NM_153704
- dbSNP
- rs199900812
- Type
- single nucleotide variant
- Location
- chr8:93755833 (GRCh38)
- Gene constraint
- LOEUF 1.079 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
- Structure
- AlphaFold pLDDT 85.20 · 1 PDB
- Residue 93
- a β-strand; the 'cysteine-rich' region; a UniProt-annotated variant site (in jbts6)
Similar variants
- TMEM67 c.1132-2A>G Likely pathogenic ★★ same condition
- TMEM67 c.223+1G>C Likely pathogenic ★★ same condition
- TMEM67 c.223+1G>T Pathogenic/Likely pathogenic ★★ same condition
- TMEM67 c.224-2A>T Pathogenic/Likely pathogenic ★★ same condition
- TMEM67 c.2556+1G>A Pathogenic ★★ same condition
- TMEM67 c.2764+2T>G Likely pathogenic ★★ same condition
- TMEM67 c.312+5G>A Pathogenic ★★ same condition
- TMEM67 c.869+1G>C Likely pathogenic ★★ same condition
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/tmem67-p-pro93 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown