NPHP4 p.Thr1004fs
c.3010dup · rs748950922 · VCV988263
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Consequence | frameshift | predicted loss-of-function |
|---|---|---|
| NMD | predicted | premature termination codon in exon 21 of 30 |
| Splicing | ||
| SpliceAI | — | not assessed · substitutions only |
| Constraint at this position | ||
| Conservation | phyloP 9.6 | GERP 0.76, phastCons 1 |
| Overall | ||
| CADD | 34.0 | PHRED · no single calibrated threshold — expert panels disagree |
Predicted loss-of-function is descriptive, not an applied PVS1 code.
Population frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Remaining individualsnot grpmax-eligible | 0.0048% | 20,826 |
| European (non-Finnish)grpmax | 0.0039% | 25,649 |
| Finnishnot grpmax-eligible | 0.00157% | 63,862 |
Remaining individuals 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.Thr1004fs
- Coding
- c.3010dup
- MANE Select
- NM_015102
- dbSNP
- rs748950922
- Type
- Duplication
- Location
- chr1:5874907 (GRCh38)
- Gene constraint
- LOEUF 1.183 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 72.44
- Residue 1004
- the 'sufficient for basal bodies localization' region
Disease context
nephronophthisis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatmentsFor Nephronophthisis (Orphanet):
- Inheritance
- Autosomal recessive
- Onset
- Adolescent, Adult, Antenatal, Childhood, Infancy, Neonatal
- Prevalence
- 1-9 / 100 000 (Finland)
Similar variants
- NPHP4 p.Thr1004Met Uncertain significance ★★ ⚠ same residue
- NPHP4 p.Thr1004= Conflicting classifications of pathogenicity ★ same residue
- NPHP4 p.His982fs Pathogenic ★★ same condition
- NPHP4 p.Leu970fs Pathogenic/Likely pathogenic ★★ same condition
- NPHP4 p.Ser1092fs Pathogenic ★★ same condition
- NPHP4 p.Ser251fs Pathogenic ★★ same condition
- NPHP4 c.1306_1314dup Uncertain significance ★★ same condition
- NPHP4 c.3231+7dup Likely benign ★★ 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-thr1004fs (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown