Is NPHP3 p.Thr136= (c.408G>A) pathogenic?

NPHP3 p.Thr136= (c.408G>A) is classified Conflicting classifications of pathogenicity in NPHP3 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-28). Ultra-rare (popmax 0.063%, afr); Associated with nephronophthisis.

What condition is associated with NPHP3 p.Thr136= (c.408G>A)?

NPHP3 p.Thr136= (c.408G>A) is associated with nephronophthisis, renal-hepatic-pancreatic dysplasia 1, NPHP3-related Meckel-like syndrome (ClinVar).

How common is NPHP3 p.Thr136= (c.408G>A) in the general population?

NPHP3 p.Thr136= (c.408G>A) is ultra-rare (popmax 0.063%, afr) (gnomAD).

How is Nephronophthisis inherited?

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

NPHP3 p.Thr136=

c.408G>A · rs141410951 · VCV284322

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.063%, 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 -0.67	GERP -3.1
Overall
CADD	4.843	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.063% African / African-American · 47/74,578 alleles

Filtering AF 0.0486% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0436%

Overall 0.0166% 264/1,588,844 alleles · ultra-rare exomes 226/1,437,164 · genomes 38/151,680 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.063%	1,587
Middle Eastern	0.051%	1,962
Admixed American	0.0186%	5,366
South Asian	0.0183%	5,465
European (non-Finnish)	0.0153%	6,545
Remaining individualsnot grpmax-eligible	0.0147%	6,797

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.Thr136=
Coding: c.408G>A
MANE Select: NM_153240
dbSNP: rs141410951
Type: single nucleotide variant
Location: chr3:132719816 (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.Thr136fs Pathogenic/Likely pathogenic ★★ same residue
NPHP3 p.Thr136Pro 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

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-thr136 (accessed [today's date]).

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