Is NPHP3 p.Phe798Leu (c.2394C>G) pathogenic?

NPHP3 p.Phe798Leu (c.2394C>G) is classified Uncertain significance in NPHP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-06). AlphaMissense: likely benign (0.2446); Very rare (popmax 0.00533%, afr).

How common is NPHP3 p.Phe798Leu (c.2394C>G) in the general population?

NPHP3 p.Phe798Leu (c.2394C>G) is very rare (popmax 0.00533%, afr) (gnomAD).

What do computational predictors say about NPHP3 p.Phe798Leu (c.2394C>G)?

AlphaMissense predicts likely benign (score 0.2446) — an in-silico prediction, not a clinical call.

NPHP3 p.Phe798Leu

c.2394C>G · rs534190640 · VCV1704625

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2446 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00533%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2446	likely benign
REVEL	0.099	moderately benign-leaning
SaProt	LLR -3.88	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.4	GERP -1.4, phastCons 0.94
Regional constraint	o/e 0.88	unconstrained · MANE · 11 kb · p 0.0019 · regional, not allelic
Overall
CADD	16.21	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00533% African / African-American · 4/75,046 alleles

Filtering AF 0.00174% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00031% 5/1,614,014 alleles · very rare exomes 2/1,461,698 · genomes 3/152,316 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00533%	18,762
South Asian	0.0011%	91,084

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.Phe798Leu
Coding: c.2394C>G
MANE Select: NM_153240
dbSNP: rs534190640
Type: single nucleotide variant
Location: chr3:132692735 (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

Similar variants

NPHP3 p.Phe798= Likely benign ★ same residue
NPHP3 c.1985+1G>A Pathogenic/Likely pathogenic ★★ same type
NPHP3 c.3201+1G>T Likely pathogenic ★★ same type
NPHP3 c.393+1G>C Likely pathogenic ★★ same type
NPHP3 c.520-1G>T Pathogenic ★★ same type
NPHP3 c.823+1G>T Likely pathogenic ★★ same type
NPHP3 c.958-2A>G Pathogenic ★★ same type
NPHP3 p.Arg1125Ter Pathogenic ★★ same type

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-phe798leu (accessed [today's date]).

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