Is NPHP1 p.Glu623del (c.1860AGA[2]) pathogenic?

NPHP1 p.Glu623del (c.1860AGA[2]) is classified Uncertain significance in NPHP1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-04-19). Very rare (popmax 0.00661%, nfe); Associated with Joubert syndrome with renal defect.

What condition is associated with NPHP1 p.Glu623del (c.1860AGA[2])?

NPHP1 p.Glu623del (c.1860AGA[2]) is associated with Joubert syndrome with renal defect, nephronophthisis 1, Senior-Loken syndrome 1 (ClinVar).

How common is NPHP1 p.Glu623del (c.1860AGA[2]) in the general population?

NPHP1 p.Glu623del (c.1860AGA[2]) is very rare (popmax 0.00661%, nfe) (gnomAD).

NPHP1 p.Glu623del

c.1860AGA[2] · rs769266828 · VCV502793

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00661%, nfe)

Conditions

Joubert syndrome with renal defect

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 2	GERP 1.9, phastCons 1
Overall
CADD	16.41	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00661% European (non-Finnish) · 78/1,180,030 alleles

Filtering AF 0.00538% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00498%

Overall 0.00508% 82/1,614,050 alleles · very rare exomes 80/1,461,862 · genomes 2/152,188 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00661%	15,129
Remaining individualsnot grpmax-eligible	0.0048%	20,827
African / African-American	0.00133%	74,924

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: NPHP1
Protein: p.Glu623del
Coding: c.1860AGA[2]
MANE Select: NM_001128178
dbSNP: rs769266828
Type: Microsatellite
Location: chr2:110123957 (GRCh38)
Gene constraint: LOEUF 0.92 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.22 · 2 PDB

Full NPHP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Joubert syndrome with renal defect — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: nephronophthisis 1 Senior-Loken syndrome 1

Similar variants

NPHP1 c.522+5_522+8del Uncertain significance ★★ same condition
NPHP1 p.Glu215dup Conflicting classifications of pathogenicity ★ same condition
NPHP1 p.Glu623Gln Uncertain significance ★ ⚠ same residue
NPHP1 c.1083+1G>A Likely pathogenic ★★ same condition
NPHP1 c.1270-1G>A Pathogenic ★★ same condition
NPHP1 c.1270-2A>G Pathogenic/Likely pathogenic ★★ same condition
NPHP1 c.141_143+40del Likely pathogenic ★★ same condition
NPHP1 c.143+1G>C 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/nphp1-p-glu623del (accessed [today's date]).

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