Conflicting classifications of pathogenicity
Conflicting submitters
Classification
Conflicting classifications of pathogenicity
ClinVar
Review
Conflicting submitters ★☆☆☆
ClinVar · 3 submitters
gnomAD v4.1
Rare
ultra-rare (popmax 0.0521%, nfe)
Conditions
1
lissencephaly 4
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP -9.3 | GERP -4.5 |
| Overall | ||
| CADD | 0.124 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.0521%
European (non-Finnish) · 615/1,180,026 alleles
Filtering AF
0.0486%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.0473%
Overall
0.0414%
668/1,613,350 alleles · ultra-rare
exomes 631/1,461,056 · genomes 37/152,294 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| European (non-Finnish)grpmax | 0.0521% | 1,919 |
| Remaining individualsnot grpmax-eligible | 0.0417% | 2,401 |
| African / African-American | 0.024% | 4,168 |
| South Asian | 0.00769% | 13,005 |
| Admixed American | 0.00333% | 30,009 |
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
- NDE1
- Protein
- p.Ala248=
- Coding
- c.744G>A
- MANE Select
- NM_017668
- dbSNP
- rs1123418
- Type
- single nucleotide variant
- Location
- chr16:15694205 (GRCh38)
- Gene constraint
- LOEUF 0.851 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
- Structure
- AlphaFold pLDDT 78.40 · 1 PDB
- Residue 248
- the 'interaction with cenpf' region
Similar variants
- NDE1 p.Arg220Ter Pathogenic/Likely pathogenic ★★ same condition
- NDE1 p.Arg37Ter Pathogenic ★★ same condition
- MYH11 p.Glu1344Val Uncertain significance ★★ ⚠ same condition
- NDE1 p.Ala101Val Uncertain significance ★★ ⚠ same condition
- NDE1 p.Ala208Val Uncertain significance ★★ ⚠ same condition
- NDE1 p.Arg234His Uncertain significance ★★ ⚠ same condition
- NDE1 p.Arg275Trp Uncertain significance ★★ ⚠ same condition
- NDE1 p.Arg62Gly Uncertain significance ★★ ⚠ 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/nde1-p-ala248 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown