Is NPHP4 p.Leu306Pro (c.917T>C) pathogenic?

NPHP4 p.Leu306Pro (c.917T>C) is classified Uncertain significance in NPHP4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-22). AlphaMissense: likely pathogenic (0.9768); Ultra-rare (popmax 0.0329%, mid); Associated with Inborn genetic diseases.

What condition is associated with NPHP4 p.Leu306Pro (c.917T>C)?

NPHP4 p.Leu306Pro (c.917T>C) is associated with Inborn genetic diseases (ClinVar).

How common is NPHP4 p.Leu306Pro (c.917T>C) in the general population?

NPHP4 p.Leu306Pro (c.917T>C) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

What do computational predictors say about NPHP4 p.Leu306Pro (c.917T>C)?

AlphaMissense predicts likely pathogenic (score 0.9768) — an in-silico prediction, not a clinical call.

NPHP4 p.Leu306Pro

c.917T>C · rs766268754 · VCV3201662

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9768 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9768	likely pathogenic · top 1% in NPHP4
REVEL	0.848	moderately pathogenic-leaning
SaProt	LLR -13.89	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.1, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 123 kb · p 0.49 · regional, not allelic
Overall
CADD	25.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0329% Middle Eastern · 2/6,084 alleles

Filtering AF 0.0058% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00241%

Overall 0.000496% 8/1,613,688 alleles · ultra-rare exomes 7/1,461,494 · genomes 1/152,194 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,042
European (non-Finnish)	0.000509%	196,646

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: NPHP4
Protein: p.Leu306Pro
Coding: c.917T>C
MANE Select: NM_015102
dbSNP: rs766268754
Type: single nucleotide variant
Location: chr1:5948145 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.44

Full NPHP4 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

Similar variants

NPHP4 p.Leu306= Likely benign ★ same residue
NPHP4 p.Ala1220Val Uncertain significance ★★ ⚠ same condition
NPHP4 p.Ala1263Gly Uncertain significance ★★ ⚠ same condition
NPHP4 p.Ala649Asp Uncertain significance ★★ ⚠ same condition
NPHP4 p.Ala678Thr Uncertain significance ★★ ⚠ same condition
NPHP4 p.Ala956Thr Uncertain significance ★★ ⚠ same condition
NPHP4 p.Ala988Thr Uncertain significance ★★ ⚠ same condition
NPHP4 p.Arg1109Gln Uncertain significance ★★ ⚠ 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/nphp4-p-leu306pro (accessed [today's date]).

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