NPHP3 p.Val646=
c.1938A>G · VCV4964286
Likely benign
Single submitter
Classification
Likely benign
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
very rare (popmax 0.00534%, afr)
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
|---|---|---|
| Pangolin | Δ0.31 | gain · loss 0.00 · not in the SpliceAI release · independent |
| Constraint at this position | ||
| Conservation | phyloP -1.3 | GERP -3.1 |
| Overall | ||
| CADD | 6.432 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.00534%
African / African-American · 4/74,942 alleles
Filtering AF
0.00175%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.00104%
Overall
0.000496%
8/1,612,760 alleles · very rare
exomes 6/1,460,524 · genomes 2/152,236 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| African / African-Americangrpmax | 0.00534% | 18,736 |
| European (non-Finnish) | 0.000339% | 294,972 |
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
- NPHP3
- Protein
- p.Val646=
- Coding
- c.1938A>G
- MANE Select
- NM_153240
- Type
- single nucleotide variant
- Location
- chr3:132699400 (GRCh38)
- Gene constraint
- LOEUF 0.873 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 73.59 · 1 PDB
Similar variants
- NPHP3 p.Val646Leu Uncertain significance ★ ⚠ same residue
- NPHP3 p.Val646fs Likely pathogenic ★ same residue
- NPHP3 c.1985+1G>A Pathogenic/Likely pathogenic ★★ same type
- NPHP3 c.3201+1G>T Likely pathogenic ★★ same type
- NPHP3 c.393+1G>C Likely pathogenic ★★ same type
- NPHP3 c.520-1G>T Pathogenic ★★ same type
- NPHP3 c.823+1G>T Likely pathogenic ★★ same type
- NPHP3 c.958-2A>G 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/nphp3-p-val646 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown