Is NPHP4 p.Pro511Leu (c.1532C>T) pathogenic?

NPHP4 p.Pro511Leu (c.1532C>T) is classified Uncertain significance in NPHP4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-24). AlphaMissense: likely benign (0.0948); Very rare (popmax 0.00348%, sas); Associated with nephronophthisis.

What condition is associated with NPHP4 p.Pro511Leu (c.1532C>T)?

NPHP4 p.Pro511Leu (c.1532C>T) is associated with nephronophthisis (ClinVar).

How common is NPHP4 p.Pro511Leu (c.1532C>T) in the general population?

NPHP4 p.Pro511Leu (c.1532C>T) is very rare (popmax 0.00348%, sas) (gnomAD).

How is Nephronophthisis inherited?

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

What do computational predictors say about NPHP4 p.Pro511Leu (c.1532C>T)?

AlphaMissense predicts likely benign (score 0.0948) — an in-silico prediction, not a clinical call.

NPHP4 p.Pro511Leu

c.1532C>T · rs761974713 · VCV1039129

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0948 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00348%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

nephronophthisis

Computational evidence

Protein change
AlphaMissense	0.0948	likely benign
REVEL	0.653	pathogenic-leaning
SaProt	LLR -6.77	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 8.3	GERP 2, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 123 kb · p 0.49 · regional, not allelic
Overall
CADD	22.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00348% South Asian · 3/86,230 alleles

Filtering AF 0.000924% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000726%

Overall 0.00132% 21/1,585,524 alleles · very rare exomes 19/1,433,302 · genomes 2/152,222 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00348%	28,743
Remaining individualsnot grpmax-eligible	0.00163%	61,388
European (non-Finnish)	0.00146%	68,553

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.Pro511Leu
Coding: c.1532C>T
MANE Select: NM_015102
dbSNP: rs761974713
Type: single nucleotide variant
Location: chr1:5907194 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.44
Residue 511: the 'disordered' region

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.Pro511= Conflicting classifications of pathogenicity ★ same residue
NPHP4 p.Pro511Arg 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-pro511leu (accessed [today's date]).

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