NPHP4 p.Thr459=
c.1377G>A · rs769077319 · VCV954088
Conflicting classifications of pathogenicity
Conflicting submitters
Classification
Conflicting classifications of pathogenicity
ClinVar
Review
Conflicting submitters ★☆☆☆
ClinVar · 2 submitters
gnomAD v4.1
Rare
ultra-rare (popmax 0.0164%, mid)
Conditions
2
NPHP4-related disorder
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 |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP -8.1 | GERP -3.6 |
| Overall | ||
| CADD | 0.424 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.0164%
Middle Eastern · 1/6,084 alleles
Filtering AF
0.00751%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.00593%
Overall
0.00124%
20/1,613,406 alleles · ultra-rare
exomes 19/1,461,350 · genomes 1/152,056 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Middle Easterngrpmax | 0.0164% | 6,084 |
| South Asian | 0.0132% | 7,589 |
| Remaining individualsnot grpmax-eligible | 0.00961% | 10,409 |
| European (non-Finnish) | 8.48e-05% | 1,179,546 |
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.Thr459=
- Coding
- c.1377G>A
- MANE Select
- NM_015102
- dbSNP
- rs769077319
- Type
- single nucleotide variant
- Location
- chr1:5927713 (GRCh38)
- Gene constraint
- LOEUF 1.183 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 72.44
- Residue 459
- the 'disordered' region
Similar variants
- NPHP4 p.Thr459Met Uncertain significance ★★ ⚠ same residue
- NPHP4 p.Thr459Pro Uncertain significance ★★ ⚠ same residue
- NPHP4 p.Thr459Lys Conflicting classifications of pathogenicity ★ ⚠ 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
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-thr459 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown