NPHP1 p.Gln258His
c.774G>T · VCV4536940
Uncertain significance
Single submitter
Classification
Uncertain significance
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
very rare (popmax 8.52e-05%, nfe)
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal. | ||
| REVEL | 0.223 | benign-leaning |
|---|---|---|
| Splicing | ||
| SpliceAI | Δ0.59 | acceptor loss, 1 bp away · masked 0 · deltas |
| Pangolin | Δ0.47 | loss · gain 0.01 · agrees with SpliceAI · independent |
| Constraint at this position | ||
| Conservation | phyloP 2.1 | GERP 1.7, phastCons 0.98 |
| Regional constraint | o/e 0.96 | unconstrained · MANE · 81 kb · p 0.26 · regional, not allelic |
| Overall | ||
| CADD | 24.6 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
8.52e-05%
European (non-Finnish) · 1/1,173,104 alleles
Overall
6.22e-05%
1/1,606,578 alleles · very rare
exomes 1/1,454,278 · genomes 0/152,300 · joint denominator
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
- NPHP1
- Protein
- p.Gln258His
- Coding
- c.774G>T
- MANE Select
- NM_001128178
- Type
- single nucleotide variant
- Location
- chr2:110163133 (GRCh38)
- Gene constraint
- LOEUF 0.92 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 76.22 · 2 PDB
Similar variants
- NPHP1 c.1083+1G>A Likely pathogenic ★★ same type
- NPHP1 c.1270-1G>A Pathogenic ★★ same type
- NPHP1 c.1270-2A>G Pathogenic/Likely pathogenic ★★ same type
- NPHP1 c.143+1G>C Likely pathogenic ★★ same type
- NPHP1 c.144-1G>A Pathogenic/Likely pathogenic ★★ same type
- NPHP1 c.1716+1G>T Pathogenic/Likely pathogenic ★★ same type
- NPHP1 c.329+1G>A Pathogenic/Likely pathogenic ★★ same type
- NPHP1 c.522+1G>A Likely 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/nphp1-p-gln258his (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown