Is NPHP4 p.Pro165= (c.495G>A) pathogenic?

NPHP4 p.Pro165= (c.495G>A) is classified Likely benign in NPHP4 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-15). Very rare (popmax 0.00224%, eas); Associated with nephronophthisis.

What condition is associated with NPHP4 p.Pro165= (c.495G>A)?

NPHP4 p.Pro165= (c.495G>A) is associated with nephronophthisis (ClinVar).

How common is NPHP4 p.Pro165= (c.495G>A) in the general population?

NPHP4 p.Pro165= (c.495G>A) is very rare (popmax 0.00224%, eas) (gnomAD).

How is Nephronophthisis inherited?

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

NPHP4 p.Pro165=

c.495G>A · rs767988061 · VCV2055233

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00224%, eas)

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 · C>G here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP -10	GERP -4
Overall
CADD	6.951	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00224% East Asian · 1/44,644 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000436% 7/1,606,956 alleles · very rare exomes 7/1,454,662 · genomes 0/152,294 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00224%	44,644
Admixed American	0.00169%	59,022
Remaining individualsnot grpmax-eligible	0.00161%	62,230
South Asian	0.00112%	89,068
European (non-Finnish)	0.000255%	392,435

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.Pro165=
Coding: c.495G>A
MANE Select: NM_015102
dbSNP: rs767988061
Type: single nucleotide variant
Location: chr1:5967321 (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.Pro165Leu Uncertain significance ★★ ⚠ same residue
NPHP4 p.Pro165Ser 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.518-2A>G 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-pro165 (accessed [today's date]).

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