Is NPHP4 p.Pro85Leu (c.254C>T) pathogenic?

NPHP4 p.Pro85Leu (c.254C>T) is classified Uncertain significance in NPHP4 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-01-18). AlphaMissense: likely benign (0.064); Ultra-rare (popmax 0.0405%, amr); Associated with Senior-Loken syndrome 4.

What condition is associated with NPHP4 p.Pro85Leu (c.254C>T)?

NPHP4 p.Pro85Leu (c.254C>T) is associated with Senior-Loken syndrome 4, nephronophthisis 4, nephronophthisis (ClinVar).

How common is NPHP4 p.Pro85Leu (c.254C>T) in the general population?

NPHP4 p.Pro85Leu (c.254C>T) is ultra-rare (popmax 0.0405%, amr) (gnomAD).

How is Senior-Loken syndrome inherited?

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

What do computational predictors say about NPHP4 p.Pro85Leu (c.254C>T)?

AlphaMissense predicts likely benign (score 0.064) — an in-silico prediction, not a clinical call.

NPHP4 p.Pro85Leu

c.254C>T · rs200272048 · VCV501720

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.064 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0405%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Senior-Loken syndrome 4

Computational evidence

Protein change
AlphaMissense	0.064	likely benign
REVEL	0.194	benign-leaning
SaProt	LLR -6.05	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 1.5	GERP -3.1, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 123 kb · p 0.49 · regional, not allelic
Overall
CADD	12.14	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 0.0405% Admixed American · 24/59,196 alleles

Filtering AF 0.0279% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0237%

Overall 0.00522% 84/1,608,170 alleles · ultra-rare exomes 74/1,456,038 · genomes 10/152,132 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0405%	2,466
Middle Eastern	0.0165%	6,054
South Asian	0.00999%	10,008
Remaining individualsnot grpmax-eligible	0.00803%	12,460
East Asian	0.00447%	22,349
European (non-Finnish)	0.00348%	28,723
Finnishnot grpmax-eligible	0.00318%	31,462

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.Pro85Leu
Coding: c.254C>T
MANE Select: NM_015102
dbSNP: rs200272048
Type: single nucleotide variant
Location: chr1:5978295 (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

Senior-Loken syndrome 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: nephronophthisis 4 nephronophthisis

For Senior-Loken syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood, Infancy
Prevalence: 1-9 / 1 000 000 (Worldwide)

Similar variants

NPHP4 p.Pro85= Likely benign ★ 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
NPHP4 c.518-2A>G 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-pro85leu (accessed [today's date]).

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