Is NPHP3 p.Thr1084= (c.3252A>G) pathogenic?

NPHP3 p.Thr1084= (c.3252A>G) is classified Conflicting classifications of pathogenicity in NPHP3 (ClinVar, Conflicting submitters, 10 submitters; last evaluated 2026-02-01). Low-frequency (popmax 2.11%, afr); Associated with nephronophthisis.

What condition is associated with NPHP3 p.Thr1084= (c.3252A>G)?

NPHP3 p.Thr1084= (c.3252A>G) is associated with nephronophthisis, renal-hepatic-pancreatic dysplasia 1, NPHP3-related Meckel-like syndrome (ClinVar).

How common is NPHP3 p.Thr1084= (c.3252A>G) in the general population?

NPHP3 p.Thr1084= (c.3252A>G) is low-frequency (popmax 2.11%, afr) (gnomAD).

How is Nephronophthisis inherited?

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

NPHP3 p.Thr1084=

c.3252A>G · rs11915053 · VCV262704

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 10 submitters

gnomAD v4.1

Rare

low-frequency (popmax 2.11%, afr)

Conditions

nephronophthisis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -20	GERP -3.6
Overall
CADD	0.168	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.11% African / African-American · 1,582/75,044 alleles

Filtering AF 2.02% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.99%

Overall 0.112% 1,803/1,613,968 alleles · low-frequency exomes 920/1,461,662 · genomes 883/152,306 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.11%	47
Remaining individualsnot grpmax-eligible	0.147%	679
Admixed American	0.13%	770
Middle Eastern	0.0495%	2,019
European (non-Finnish)	0.00373%	26,814
South Asian	0.00329%	30,363
Finnishnot grpmax-eligible	0.00156%	64,036

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.Thr1084=
Coding: c.3252A>G
MANE Select: NM_153240
dbSNP: rs11915053
Type: single nucleotide variant
Location: chr3:132686337 (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 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
NPHP3 p.Arg1259Ter Pathogenic/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/nphp3-p-thr1084 (accessed [today's date]).

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