Is NPHP3 p.Thr493Ala (c.1477A>G) pathogenic?

NPHP3 p.Thr493Ala (c.1477A>G) is classified Conflicting classifications of pathogenicity in NPHP3 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-11-24). AlphaMissense: likely benign (0.0523); Very rare (popmax 0.00801%, afr); Associated with Inborn genetic diseases.

What condition is associated with NPHP3 p.Thr493Ala (c.1477A>G)?

NPHP3 p.Thr493Ala (c.1477A>G) is associated with Inborn genetic diseases, nephronophthisis (ClinVar).

How common is NPHP3 p.Thr493Ala (c.1477A>G) in the general population?

NPHP3 p.Thr493Ala (c.1477A>G) is very rare (popmax 0.00801%, afr) (gnomAD).

What do computational predictors say about NPHP3 p.Thr493Ala (c.1477A>G)?

AlphaMissense predicts likely benign (score 0.0523) — an in-silico prediction, not a clinical call.

NPHP3 p.Thr493Ala

c.1477A>G · rs369600509 · VCV2067414

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0523 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00801%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0523	likely benign
REVEL	0.217	benign-leaning
SaProt	LLR -4.65	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 -0.51	GERP -4, phastCons 0.022
Regional constraint	o/e 1.01	unconstrained · MANE · 30 kb · p 0.87 · regional, not allelic
Overall
CADD	9.415	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 0.00801% African / African-American · 6/74,936 alleles

Filtering AF 0.00347% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00228%

Overall 0.000372% 6/1,614,078 alleles · very rare exomes 3/1,461,876 · genomes 3/152,202 · joint denominator

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.Thr493Ala
Coding: c.1477A>G
MANE Select: NM_153240
dbSNP: rs369600509
Type: single nucleotide variant
Location: chr3:132704245 (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: 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.958-2A>G Pathogenic ★★ same condition
NPHP3 p.Arg1125Ter Pathogenic ★★ same condition
NPHP3 p.Arg1259Ter Pathogenic/Likely pathogenic ★★ same condition
NPHP3 p.Arg142Ter Pathogenic/Likely pathogenic ★★ same condition
NPHP3 p.Arg577Ter 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-thr493ala (accessed [today's date]).

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