Is NPHP3 p.Tyr509His (c.1525T>C) pathogenic?

NPHP3 p.Tyr509His (c.1525T>C) is classified Uncertain significance in NPHP3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-07-19). AlphaMissense: ambiguous (0.5157); Ultra-rare (popmax 0.033%, mid); Associated with nephronophthisis.

What condition is associated with NPHP3 p.Tyr509His (c.1525T>C)?

NPHP3 p.Tyr509His (c.1525T>C) is associated with nephronophthisis, renal-hepatic-pancreatic dysplasia 1, NPHP3-related Meckel-like syndrome (ClinVar).

How common is NPHP3 p.Tyr509His (c.1525T>C) in the general population?

NPHP3 p.Tyr509His (c.1525T>C) is ultra-rare (popmax 0.033%, mid) (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 NPHP3 p.Tyr509His (c.1525T>C)?

AlphaMissense predicts ambiguous (score 0.5157) — an in-silico prediction, not a clinical call.

NPHP3 p.Tyr509His

c.1525T>C · rs1939605927 · VCV960492

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5157 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Conditions

nephronophthisis

Computational evidence

Protein change
AlphaMissense	0.5157	ambiguous
REVEL	0.387	indeterminate
SaProt	LLR -7.97	tolerated
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 0.64, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 30 kb · p 0.87 · regional, not allelic
Overall
CADD	23.8	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 0.033% Middle Eastern · 2/6,066 alleles

Filtering AF 0.00581% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00242%

Overall 0.000936% 15/1,601,912 alleles · ultra-rare exomes 14/1,449,754 · genomes 1/152,158 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,033
South Asian	0.00551%	18,165
Remaining individualsnot grpmax-eligible	0.00322%	31,022
East Asian	0.00223%	44,822
European (non-Finnish)	0.000428%	233,820

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: NPHP3
Protein: p.Tyr509His
Coding: c.1525T>C
MANE Select: NM_153240
dbSNP: rs1939605927
Type: single nucleotide variant
Location: chr3:132701533 (GRCh38)
Gene constraint: LOEUF 0.873 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.59 · 1 PDB

Full NPHP3 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

Also linked: renal-hepatic-pancreatic dysplasia 1 NPHP3-related Meckel-like syndrome nephronophthisis 3

For Nephronophthisis (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Antenatal, Childhood, Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Finland)

Similar variants

NPHP3 p.Tyr509Cys Uncertain significance ★ same residue
NPHP3 c.1985+1G>A Pathogenic/Likely pathogenic ★★ same condition
NPHP3 c.3201+1G>T Likely pathogenic ★★ same condition
NPHP3 c.393+1G>C Likely pathogenic ★★ same condition
NPHP3 c.520-1G>T Pathogenic ★★ same condition
NPHP3 c.823+1G>T Likely pathogenic ★★ same condition
NPHP3 c.958-2A>G Pathogenic ★★ same condition
NPHP3 p.Arg1125Ter 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/nphp3-p-tyr509his (accessed [today's date]).

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