Is NPHP4 p.Tyr667fs (c.1998_1999del) pathogenic?

NPHP4 p.Tyr667fs (c.19981999del) is classified Pathogenic in NPHP4 (ClinVar, Single submitter, 2 submitters; last evaluated 2020-07-22). Very rare (popmax 0.00223%, eas); Associated with nephronophthisis.

What condition is associated with NPHP4 p.Tyr667fs (c.1998_1999del)?

NPHP4 p.Tyr667fs (c.1998_1999del) is associated with nephronophthisis (ClinVar).

How common is NPHP4 p.Tyr667fs (c.1998_1999del) in the general population?

NPHP4 p.Tyr667fs (c.1998_1999del) is very rare (popmax 0.00223%, eas) (gnomAD).

How is Nephronophthisis inherited?

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

NPHP4 p.Tyr667fs

c.1998_1999del · rs1644833186 · VCV988262

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

nephronophthisis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 16 of 30
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 3.3	GERP 0.68, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,878 alleles

Filtering AF 0.000763% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000605%

Overall 0.000991% 16/1,613,920 alleles · very rare exomes 16/1,461,706 · genomes 0/152,214 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,878
European (non-Finnish)	0.00127%	78,658

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.Tyr667fs
Coding: c.1998_1999del
MANE Select: NM_015102
dbSNP: rs1644833186
Type: Microsatellite
Location: chr1:5904761 (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

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

NPHP4 p.Val1123fs Pathogenic/Likely pathogenic ★★ same condition
NPHP4 p.Val582del Uncertain significance ★★ same condition
NPHP4 p.Arg20fs Pathogenic ★ same condition
NPHP4 p.His1267fs Pathogenic ★ same condition
NPHP4 c.1764-7_1764-6del Likely benign ★ same condition
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

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-tyr667fs (accessed [today's date]).

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