Is NPHP3 p.Ile183Thr (c.548T>C) pathogenic?

NPHP3 p.Ile183Thr (c.548T>C) is classified Uncertain significance in NPHP3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-10-25). AlphaMissense: likely pathogenic (0.9953); Ultra-rare (popmax 0.044%, sas); Associated with Inborn genetic diseases.

What condition is associated with NPHP3 p.Ile183Thr (c.548T>C)?

NPHP3 p.Ile183Thr (c.548T>C) is associated with Inborn genetic diseases, nephronophthisis (ClinVar).

How common is NPHP3 p.Ile183Thr (c.548T>C) in the general population?

NPHP3 p.Ile183Thr (c.548T>C) is ultra-rare (popmax 0.044%, sas) (gnomAD).

What do computational predictors say about NPHP3 p.Ile183Thr (c.548T>C)?

AlphaMissense predicts likely pathogenic (score 0.9953) — an in-silico prediction, not a clinical call.

NPHP3 p.Ile183Thr

c.548T>C · rs563850993 · VCV1461332

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9953 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.044%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9953	likely pathogenic · top 1% in NPHP3
REVEL	0.694	pathogenic-leaning
SaProt	LLR -8.74	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.3	GERP 2, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 30 kb · p 0.87 · regional, not allelic
Overall
CADD	25.5	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 0.044% South Asian · 40/90,846 alleles

Filtering AF 0.0332% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0294%

Overall 0.00248% 40/1,612,694 alleles · ultra-rare exomes 35/1,460,416 · genomes 5/152,278 · 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.Ile183Thr
Coding: c.548T>C
MANE Select: NM_153240
dbSNP: rs563850993
Type: single nucleotide variant
Location: chr3:132719116 (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-ile183thr (accessed [today's date]).

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