KRT12 p.Leu146Pro
c.437T>C · VCV4738359
Computational evidence
| Protein change | ||
| AlphaMissense | 0.9409 | likely pathogenic · top 1% in KRT12 |
|---|---|---|
| REVEL | 0.897 | moderately pathogenic-leaning |
| SaProt | LLR -16.32 | damaging |
| ⇒ AlphaMissense, REVEL and SaProt all call this damaging. | ||
| Splicing | ||
| SpliceAI | <0.2 | no splice effect predicted · four deltas, not one · how we know |
| Constraint at this position | ||
| Conservation | phyloP 11 | GERP 2, phastCons 1 |
| Regional constraint | o/e 0.94 | unconstrained · MANE · 5,522 bp · p 0.13 · regional, not allelic |
| Overall | ||
| CADD | 29.0 | PHRED · no single calibrated threshold — expert panels disagree |
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
Population frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Ashkenazi Jewishnot grpmax-eligible | 0.463% | 216 |
| Remaining individualsnot grpmax-eligible | 0.0272% | 3,676 |
| Admixed Americangrpmax | 0.0217% | 4,616 |
| European (non-Finnish) | 0.00356% | 28,096 |
| African / African-American | 0.00133% | 74,928 |
Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.
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
- KRT12
- Protein
- p.Leu146Pro
- Coding
- c.437T>C
- MANE Select
- NM_000223
- Type
- single nucleotide variant
- Location
- chr17:40866750 (GRCh38)
- Gene constraint
- LOEUF 0.979 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 74.57
- Residue 146
- the if rod domain; the 'coil 1a' region
Similar variants
- KRT12 p.Met129Val Pathogenic/Likely pathogenic ★★ same type
- KRT12 p.Asp213Tyr Uncertain significance ★★ ⚠ same type
- KRT12 p.Gln486Glu Uncertain significance ★★ ⚠ same type
- KRT12 p.Ile195Phe Uncertain significance ★★ ⚠ same type
- KRT12 p.Val228Ile Uncertain significance ★★ ⚠ same type
- KRT12 c.808-17T>A Benign/Likely benign ★★ same type
- KRT12 p.Arg20Trp Benign ★★ ⚠ same type
- KRT12 p.Gln475Arg Likely benign ★★ ⚠ 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/krt12-p-leu146pro (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown