Is NPHP4 p.Gln45Ter (c.133C>T) pathogenic?

NPHP4 p.Gln45Ter (c.133C>T) is classified Pathogenic/Likely pathogenic in NPHP4 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2025-12-10). Ultra-rare (popmax 0.012%, nfe); Associated with inherited retinal dystrophy.

What condition is associated with NPHP4 p.Gln45Ter (c.133C>T)?

NPHP4 p.Gln45Ter (c.133C>T) is associated with inherited retinal dystrophy, nephronophthisis 4, Senior-Loken syndrome 4 (ClinVar).

How common is NPHP4 p.Gln45Ter (c.133C>T) in the general population?

NPHP4 p.Gln45Ter (c.133C>T) is ultra-rare (popmax 0.012%, nfe) (gnomAD).

NPHP4 p.Gln45Ter

c.133C>T · rs370210428 · VCV562355

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.012%, nfe)

Conditions

inherited retinal dystrophy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 2 of 30
Splicing
SpliceAI	Δ0.95	donor gain · deltas
Pangolin	Δ0.82	gain · loss 0.73 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 11	GERP 2.1, phastCons 1
Overall
CADD	54.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.012% European (non-Finnish) · 141/1,179,834 alleles

Filtering AF 0.0103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00972%

Overall 0.00892% 144/1,613,652 alleles · ultra-rare exomes 139/1,461,494 · genomes 5/152,158 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.012%	8,368
Remaining individualsnot grpmax-eligible	0.0032%	31,227
African / African-American	0.00134%	74,884

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.Gln45Ter
Coding: c.133C>T
MANE Select: NM_015102
dbSNP: rs370210428
Type: single nucleotide variant
Location: chr1:5986157 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.44

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

Disease context

inherited retinal dystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: nephronophthisis 4 Senior-Loken syndrome 4 nephronophthisis

Similar variants

NPHP4 p.Gln45Arg Uncertain significance ★ ⚠ same residue
NPHP4 p.Gln45Leu 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

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-gln45ter (accessed [today's date]).

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