Is NPHP4 p.His1056= (c.3168C>T) pathogenic?

NPHP4 p.His1056= (c.3168C>T) is classified Conflicting classifications of pathogenicity in NPHP4 (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-01-14). Rare (popmax 0.109%, nfe); Associated with nephronophthisis.

What condition is associated with NPHP4 p.His1056= (c.3168C>T)?

NPHP4 p.His1056= (c.3168C>T) is associated with nephronophthisis, nephronophthisis 4, Senior-Loken syndrome 4 (ClinVar).

How common is NPHP4 p.His1056= (c.3168C>T) in the general population?

NPHP4 p.His1056= (c.3168C>T) is rare (popmax 0.109%, nfe) (gnomAD).

How is Nephronophthisis inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

NPHP4 p.His1056=

c.3168C>T · rs376351293 · VCV288722

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

rare (popmax 0.109%, nfe)

Conditions

nephronophthisis

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 0.31	GERP -3.9, phastCons 0.2
Overall
CADD	10.35	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.109% European (non-Finnish) · 1,278/1,171,538 alleles

Filtering AF 0.104% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.102%

Overall 0.0953% 1,520/1,595,674 alleles · rare exomes 1,405/1,443,330 · genomes 115/152,344 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.279%	359
European (non-Finnish)grpmax	0.109%	917
Remaining individualsnot grpmax-eligible	0.0859%	1,165
South Asian	0.0705%	1,417
Admixed American	0.0416%	2,402
African / African-American	0.0174%	5,736
Middle Eastern	0.0166%	6,018
Finnishnot grpmax-eligible	0.0112%	8,895
East Asian	0.00227%	44,018

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.His1056=
Coding: c.3168C>T
MANE Select: NM_015102
dbSNP: rs376351293
Type: single nucleotide variant
Location: chr1:5874534 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.44
Residue 1056: the 'sufficient for basal bodies localization' region

Full NPHP4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

nephronophthisis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: nephronophthisis 4 Senior-Loken syndrome 4

For Nephronophthisis (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Antenatal, Childhood, Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Finland)

Similar variants

NPHP4 p.His1056Gln 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
NPHP4 c.518-2A>G 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-his1056 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown