Is NPHP3 p.His1235= (c.3705C>T) pathogenic?

NPHP3 p.His1235= (c.3705C>T) is classified Likely benign in NPHP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-23). Very rare (popmax 0.00154%, nfe); Associated with nephronophthisis.

What condition is associated with NPHP3 p.His1235= (c.3705C>T)?

NPHP3 p.His1235= (c.3705C>T) is associated with nephronophthisis (ClinVar).

How common is NPHP3 p.His1235= (c.3705C>T) in the general population?

NPHP3 p.His1235= (c.3705C>T) is very rare (popmax 0.00154%, nfe) (gnomAD).

How is Nephronophthisis inherited?

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

NPHP3 p.His1235=

c.3705C>T · rs753143081 · VCV703627

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00154%, nfe)

Conditions

nephronophthisis

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>C here scores Δ0.69 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.35	GERP -3.1, phastCons 0.008
Overall
CADD	6.366	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00154% European (non-Finnish) · 18/1,170,920 alleles

Filtering AF 0.000961% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000793%

Overall 0.00168% 27/1,603,850 alleles · very rare exomes 25/1,451,814 · genomes 2/152,036 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0203%	4,925
Remaining individualsnot grpmax-eligible	0.00322%	31,072
European (non-Finnish)grpmax	0.00154%	65,051
South Asian	0.0011%	90,834

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: NPHP3
Protein: p.His1235=
Coding: c.3705C>T
MANE Select: NM_153240
dbSNP: rs753143081
Type: single nucleotide variant
Location: chr3:132682810 (GRCh38)
Gene constraint: LOEUF 0.873 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.59 · 1 PDB

Full NPHP3 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

For Nephronophthisis (Orphanet):

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

Similar variants

NPHP3 c.1985+1G>A Pathogenic/Likely pathogenic ★★ same condition
NPHP3 c.3201+1G>T Likely pathogenic ★★ same condition
NPHP3 c.393+1G>C Likely pathogenic ★★ same condition
NPHP3 c.958-2A>G Pathogenic ★★ same condition
NPHP3 p.Arg1125Ter Pathogenic ★★ same condition
NPHP3 p.Arg1259Ter Pathogenic/Likely pathogenic ★★ same condition
NPHP3 p.Arg142Ter Pathogenic/Likely pathogenic ★★ same condition
NPHP3 p.Arg577Ter 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/nphp3-p-his1235 (accessed [today's date]).

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