Is NPHP3 p.Glu833Gln (c.2497G>C) pathogenic?

NPHP3 p.Glu833Gln (c.2497G>C) is classified Conflicting classifications of pathogenicity in NPHP3 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-12). AlphaMissense: likely benign (0.1541); Ultra-rare (popmax 0.0203%, nfe); Associated with Inborn genetic diseases.

What condition is associated with NPHP3 p.Glu833Gln (c.2497G>C)?

NPHP3 p.Glu833Gln (c.2497G>C) is associated with Inborn genetic diseases, renal-hepatic-pancreatic dysplasia 1, NPHP3-related Meckel-like syndrome (ClinVar).

How common is NPHP3 p.Glu833Gln (c.2497G>C) in the general population?

NPHP3 p.Glu833Gln (c.2497G>C) is ultra-rare (popmax 0.0203%, nfe) (gnomAD).

What do computational predictors say about NPHP3 p.Glu833Gln (c.2497G>C)?

AlphaMissense predicts likely benign (score 0.1541) — an in-silico prediction, not a clinical call.

NPHP3 p.Glu833Gln

c.2497G>C · rs142084136 · VCV999580

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1541 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0203%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1541	likely benign
REVEL	0.25	benign-leaning
SaProt	LLR -7.16	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.9	GERP 1.6, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 11 kb · p 0.0019 · regional, not allelic
Overall
CADD	19.17	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 0.0203% European (non-Finnish) · 239/1,179,072 alleles

Filtering AF 0.0181% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0173%

Overall 0.0156% 252/1,612,764 alleles · ultra-rare exomes 238/1,460,684 · genomes 14/152,080 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0203%	4,933
Remaining individualsnot grpmax-eligible	0.00801%	12,486
Finnishnot grpmax-eligible	0.00625%	16,002
African / African-American	0.00534%	18,719

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.Glu833Gln
Coding: c.2497G>C
MANE Select: NM_153240
dbSNP: rs142084136
Type: single nucleotide variant
Location: chr3:132691265 (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

Inborn genetic diseases — 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 nephronophthisis

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-glu833gln (accessed [today's date]).

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