Is NPHP4 p.Pro86Leu (c.257C>T) pathogenic?

NPHP4 p.Pro86Leu (c.257C>T) is classified Uncertain significance in NPHP4 (ClinVar, Multiple submitters, 10 submitters; last evaluated 2025-05-19). AlphaMissense: likely benign (0.0708); Ultra-rare (popmax 0.0709%, amr); Associated with nephronophthisis 4.

What condition is associated with NPHP4 p.Pro86Leu (c.257C>T)?

NPHP4 p.Pro86Leu (c.257C>T) is associated with nephronophthisis 4, optic atrophy, kidney disorder (ClinVar).

How common is NPHP4 p.Pro86Leu (c.257C>T) in the general population?

NPHP4 p.Pro86Leu (c.257C>T) is ultra-rare (popmax 0.0709%, amr) (gnomAD).

How is Nephronophthisis inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about NPHP4 p.Pro86Leu (c.257C>T)?

AlphaMissense predicts likely benign (score 0.0708) — an in-silico prediction, not a clinical call.

NPHP4 p.Pro86Leu

c.257C>T · rs201998215 · VCV297830

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

AlphaMissense

likely benign

0.0708 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0709%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

nephronophthisis 4

Computational evidence

Protein change
AlphaMissense	0.0708	likely benign
REVEL	0.26	benign-leaning
SaProt	LLR -5.83	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.5	GERP -0.54, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 123 kb · p 0.49 · regional, not allelic
Overall
CADD	19.02	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 0.0709% Admixed American · 42/59,212 alleles

Filtering AF 0.0539% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.048%

Overall 0.0197% 317/1,608,102 alleles · ultra-rare exomes 276/1,455,950 · genomes 41/152,152 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0709%	1,410
European (non-Finnish)	0.0217%	4,600
African / African-American	0.0147%	6,808
Remaining individualsnot grpmax-eligible	0.0112%	8,900
East Asian	0.00224%	44,668

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.Pro86Leu
Coding: c.257C>T
MANE Select: NM_015102
dbSNP: rs201998215
Type: single nucleotide variant
Location: chr1:5978292 (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

nephronophthisis 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: optic atrophy kidney disorder Senior-Loken syndrome 4 nephronophthisis

For Nephronophthisis (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Antenatal, Childhood, Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Finland)

Similar variants

NPHP4 p.Pro86= Likely benign ★ same residue
NPHP4 p.Pro86fs Pathogenic ★ same residue
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

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-pro86leu (accessed [today's date]).

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