NPHP4 p.Ser224=
c.672C>T · rs899131824 · VCV502563
Conflicting classifications of pathogenicity
Conflicting submitters
Classification
Conflicting classifications of pathogenicity
ClinVar
Review
Conflicting submitters ★☆☆☆
ClinVar · 2 submitters
gnomAD v4.1
Rare
very rare (popmax 0.00664%, sas)
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Splicing | ||
| SpliceAI | <0.2 | all four deltas below 0.2 · G>T here scores Δ0.34 · evaluated, not missing |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP -11 | GERP -4 |
| Overall | ||
| CADD | 0.037 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.00664%
South Asian · 6/90,360 alleles
Filtering AF
0.00288%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.00196%
Overall
0.00223%
36/1,610,764 alleles · very rare
exomes 32/1,458,536 · genomes 4/152,228 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| South Asiangrpmax | 0.00664% | 15,060 |
| Remaining individualsnot grpmax-eligible | 0.00321% | 31,180 |
| European (non-Finnish) | 0.00229% | 43,647 |
| Admixed American | 0.00168% | 59,552 |
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.Ser224=
- Coding
- c.672C>T
- MANE Select
- NM_015102
- dbSNP
- rs899131824
- Type
- single nucleotide variant
- Location
- chr1:5961795 (GRCh38)
- Gene constraint
- LOEUF 1.183 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 72.44
Similar variants
- NPHP4 p.Ser224Cys Uncertain significance ★ ⚠ same residue
- NPHP4 c.2304+1G>A Pathogenic ★★ same type
- NPHP4 c.2611+1G>A Pathogenic/Likely pathogenic ★★ same type
- NPHP4 c.2611+1G>C Pathogenic ★★ same type
- NPHP4 c.3644+1G>A Pathogenic/Likely pathogenic ★★ same type
- NPHP4 c.3644+1G>T Pathogenic/Likely pathogenic ★★ same type
- NPHP4 c.517+1G>A Pathogenic/Likely pathogenic ★★ same type
- NPHP4 c.518-2A>G 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/nphp4-p-ser224 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown