Is NPHP4 p.Leu48Pro (c.143T>C) pathogenic?

NPHP4 p.Leu48Pro (c.143T>C) is classified Uncertain significance in NPHP4 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-11-19). AlphaMissense: likely benign (0.0874); Very rare (popmax 0.00707%, nfe); Associated with Inborn genetic diseases.

What condition is associated with NPHP4 p.Leu48Pro (c.143T>C)?

NPHP4 p.Leu48Pro (c.143T>C) is associated with Inborn genetic diseases, nephronophthisis 4, Senior-Loken syndrome 4 (ClinVar).

How common is NPHP4 p.Leu48Pro (c.143T>C) in the general population?

NPHP4 p.Leu48Pro (c.143T>C) is very rare (popmax 0.00707%, nfe) (gnomAD).

What do computational predictors say about NPHP4 p.Leu48Pro (c.143T>C)?

AlphaMissense predicts likely benign (score 0.0874) — an in-silico prediction, not a clinical call.

NPHP4 p.Leu48Pro

c.143T>C · rs374239338 · VCV1040891

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0874 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00707%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0874	likely benign
REVEL	0.341	indeterminate
SaProt	LLR -6.82	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.7	GERP 0.61, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 123 kb · p 0.49 · regional, not allelic
Overall
CADD	19.42	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 0.00707% European (non-Finnish) · 83/1,174,724 alleles

Filtering AF 0.00582% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00535%

Overall 0.00549% 88/1,602,430 alleles · very rare exomes 83/1,450,256 · genomes 5/152,174 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00707%	14,153
Remaining individualsnot grpmax-eligible	0.00322%	31,053
African / African-American	0.00268%	37,323
Admixed American	0.00171%	58,434

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.Leu48Pro
Coding: c.143T>C
MANE Select: NM_015102
dbSNP: rs374239338
Type: single nucleotide variant
Location: chr1:5978406 (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

Also linked: nephronophthisis 4 Senior-Loken syndrome 4 nephronophthisis

Similar variants

NPHP4 c.2304+1G>A Pathogenic ★★ same condition
NPHP4 c.2611+1G>A Pathogenic/Likely pathogenic ★★ same condition
NPHP4 c.2611+1G>C Pathogenic ★★ same condition
NPHP4 c.3644+1G>A Pathogenic/Likely pathogenic ★★ same condition
NPHP4 c.3644+1G>T Pathogenic/Likely pathogenic ★★ same condition
NPHP4 c.517+1G>A Pathogenic/Likely pathogenic ★★ same condition
NPHP4 c.518-2A>G Likely pathogenic ★★ same condition
NPHP4 c.992+2T>C Likely 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/nphp4-p-leu48pro (accessed [today's date]).

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