Is NPHP3 p.Ile618Thr (c.1853T>C) pathogenic?

NPHP3 p.Ile618Thr (c.1853T>C) is classified Conflicting classifications of pathogenicity in NPHP3 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-01-14). AlphaMissense: likely pathogenic (0.7971); Rare (popmax 0.294%, sas); Associated with renal-hepatic-pancreatic dysplasia 1.

What condition is associated with NPHP3 p.Ile618Thr (c.1853T>C)?

NPHP3 p.Ile618Thr (c.1853T>C) is associated with renal-hepatic-pancreatic dysplasia 1, NPHP3-related Meckel-like syndrome, nephronophthisis 3 (ClinVar).

How common is NPHP3 p.Ile618Thr (c.1853T>C) in the general population?

NPHP3 p.Ile618Thr (c.1853T>C) is rare (popmax 0.294%, sas) (gnomAD).

What do computational predictors say about NPHP3 p.Ile618Thr (c.1853T>C)?

AlphaMissense predicts likely pathogenic (score 0.7971) — an in-silico prediction, not a clinical call.

NPHP3 p.Ile618Thr

c.1853T>C · rs139730838 · VCV343386

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.7971 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.294%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

renal-hepatic-pancreatic dysplasia 1

Computational evidence

Protein change
AlphaMissense	0.7971	likely pathogenic
REVEL	0.594	indeterminate
SaProt	LLR -9.10	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.3	GERP 1.9, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 30 kb · p 0.87 · regional, not allelic
Overall
CADD	25.3	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 0.294% South Asian · 268/91,088 alleles

Filtering AF 0.265% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.254%

Overall 0.0447% 722/1,614,164 alleles · rare exomes 675/1,461,852 · genomes 47/152,312 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.294%	340
Middle Eastern	0.0495%	2,021
Finnishnot grpmax-eligible	0.039%	2,561
European (non-Finnish)	0.0335%	2,987
Remaining individualsnot grpmax-eligible	0.032%	3,125
Admixed American	0.015%	6,669
East Asian	0.00223%	44,876
African / African-American	0.00133%	75,042

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.Ile618Thr
Coding: c.1853T>C
MANE Select: NM_153240
dbSNP: rs139730838
Type: single nucleotide variant
Location: chr3:132699952 (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

renal-hepatic-pancreatic dysplasia 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: NPHP3-related Meckel-like syndrome nephronophthisis 3 nephronophthisis

Similar variants

NPHP3 p.Ile618Leu 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
NPHP3 p.Arg1125Ter 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-ile618thr (accessed [today's date]).

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