Is NPHP1 p.Ser129del (c.385_387del) pathogenic?

NPHP1 p.Ser129del (c.385387del) is classified Uncertain significance in NPHP1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-07-31). Very rare (popmax 0.00668%, afr); Associated with nephronophthisis.

What condition is associated with NPHP1 p.Ser129del (c.385_387del)?

NPHP1 p.Ser129del (c.385_387del) is associated with nephronophthisis (ClinVar).

How common is NPHP1 p.Ser129del (c.385_387del) in the general population?

NPHP1 p.Ser129del (c.385_387del) is very rare (popmax 0.00668%, afr) (gnomAD).

How is Nephronophthisis inherited?

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

NPHP1 p.Ser129del

c.385_387del · rs753643526 · VCV497957

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00668%, afr)

Conditions

nephronophthisis

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 -1.7	GERP -2.7
Overall
CADD	7.376	PHRED · no single calibrated threshold — expert panels disagree
Region caveats
Repeat context	tandem	(TTCCTC)n simple repeat · ambiguous alignment · confidence, not pathogenicity

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00668% African / African-American · 5/74,822 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00162%

Overall 0.000935% 15/1,603,746 alleles · very rare exomes 14/1,451,544 · genomes 1/152,202 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00668%	14,964
East Asian	0.00223%	44,804
Admixed American	0.00167%	59,944
Remaining individualsnot grpmax-eligible	0.00161%	62,122
Finnishnot grpmax-eligible	0.00156%	63,908
South Asian	0.0011%	90,850
European (non-Finnish)	0.000427%	234,160

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.Ser129del
Coding: c.385_387del
MANE Select: NM_001128178
dbSNP: rs753643526
Type: Deletion
Location: chr2:110169941 (GRCh38)
Gene constraint: LOEUF 0.92 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.22 · 2 PDB
Residue 129: the 'disordered' region

Full NPHP1 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

NPHP1 p.Ser129fs Pathogenic/Likely pathogenic ★★ same residue
NPHP1 p.Ser129Thr Uncertain significance ★ ⚠ same residue
NPHP1 c.141_143+40del Likely pathogenic ★★ same condition
NPHP1 p.Asn61fs Pathogenic/Likely pathogenic ★★ same condition
NPHP1 p.Asp162fs Pathogenic/Likely pathogenic ★★ same condition
NPHP1 p.Glu454fs Pathogenic ★★ same condition
NPHP1 p.Ile517fs Pathogenic ★★ same condition
NPHP1 p.Lys185fs 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-ser129del (accessed [today's date]).

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