NPHP4 p.Val874Met
c.2620G>A · rs1412960310 · VCV500153
Computational evidence
| Protein change | ||
| AlphaMissense | 0.2437 | likely benign |
|---|---|---|
| REVEL | 0.361 | indeterminate |
| SaProt | LLR -7.50 | tolerated |
| ⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate. | ||
| Splicing | ||
| SpliceAI | <0.2 | no splice effect predicted · four deltas, not one · how we know |
| Constraint at this position | ||
| Conservation | phyloP 7.5 | GERP 1.6, phastCons 1 |
| Regional constraint | o/e 1.02 | unconstrained · MANE · 123 kb · p 0.49 · regional, not allelic |
| Overall | ||
| CADD | 23.2 | PHRED · no single calibrated threshold — expert panels disagree |
ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification
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 | 0.0103% | 9,753 |
| Admixed Americangrpmax | 0.00843% | 11,858 |
| Remaining individualsnot grpmax-eligible | 0.00326% | 30,709 |
| European (non-Finnish) | 0.00163% | 61,244 |
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
- NPHP4
- Protein
- p.Val874Met
- Coding
- c.2620G>A
- MANE Select
- NM_015102
- dbSNP
- rs1412960310
- Type
- single nucleotide variant
- Location
- chr1:5877290 (GRCh38)
- Gene constraint
- LOEUF 1.183 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 72.44
- Residue 874
- the 'sufficient for basal bodies localization' region
Disease context
Senior-Loken syndrome 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatmentsAlso linked: nephronophthisis 4nephronophthisis
For Senior-Loken syndrome (Orphanet):
- Inheritance
- Autosomal recessive
- Onset
- Adolescent, Adult, Childhood, Infancy
- Prevalence
- 1-9 / 1 000 000 (Worldwide)
Similar variants
- NPHP4 p.Val874= Likely benign ★ same residue
- NPHP4 p.Val874Leu Uncertain significance ★ ⚠ same residue
- NPHP4 c.2304+1G>A Pathogenic ★★ same condition
- NPHP4 c.2611+1G>A Pathogenic/Likely pathogenic ★★ same condition
- NPHP4 c.2611+1G>C Pathogenic ★★ same condition
- NPHP4 c.3644+1G>A Pathogenic/Likely pathogenic ★★ same condition
- NPHP4 c.3644+1G>T Pathogenic/Likely pathogenic ★★ same condition
- NPHP4 c.517+1G>A Pathogenic/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/nphp4-p-val874met (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown