NPHP4 p.Arg740His
c.2219G>A · rs34248917 · VCV240967
Computational evidence
| Protein change | ||
| AlphaMissense | 0.0653 | likely benign |
|---|---|---|
| REVEL | 0.239 | benign-leaning |
| SaProt | LLR -7.05 | tolerated |
| ⇒ AlphaMissense, REVEL and SaProt all call this tolerated. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP -5.3 | GERP -4.1 |
| Regional constraint | o/e 1.02 | unconstrained · MANE · 123 kb · p 0.49 · regional, not allelic |
| Overall | ||
| CADD | 0.087 | 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 | 3.76% | 27 |
| Finnishnot grpmax-eligible | 3.75% | 27 |
| European (non-Finnish)grpmax | 3.26% | 31 |
| Amishnot grpmax-eligible | 2.85% | 35 |
| Remaining individualsnot grpmax-eligible | 2.72% | 37 |
| South Asian | 2.5% | 40 |
| Middle Eastern | 1.59% | 63 |
| Admixed American | 1.16% | 86 |
| African / African-American | 0.532% | 188 |
| East Asian | 0.0517% | 1,934 |
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.Arg740His
- Coding
- c.2219G>A
- MANE Select
- NM_015102
- dbSNP
- rs34248917
- Type
- single nucleotide variant
- Location
- chr1:5890953 (GRCh38)
- Gene constraint
- LOEUF 1.183 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 72.44
- Residue 740
- a UniProt-annotated variant site (does not affect interaction with rpgrip1l; does not affect interaction with rpgrip1)
Disease context
nephronophthisis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatmentsAlso linked: nephronophthisis 4Senior-Loken syndrome 4Bardet-Biedl syndromeatypical hemolytic-uremic syndrome
For Nephronophthisis (Orphanet):
- Inheritance
- Autosomal recessive
- Onset
- Adolescent, Adult, Antenatal, Childhood, Infancy, Neonatal
- Prevalence
- 1-9 / 100 000 (Finland)
Similar variants
- NPHP4 p.Arg740Cys Uncertain significance ★★ ⚠ same residue
- NPHP4 p.Arg740Gly 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-arg740his (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown