Is NPHP4 p.Lys809Arg (c.2426A>G) pathogenic?

NPHP4 p.Lys809Arg (c.2426A>G) is classified Uncertain significance in NPHP4 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2022-10-26). AlphaMissense: likely benign (0.08); Very rare (popmax 0.0061%, nfe); Associated with NPHP4-related disorder.

What condition is associated with NPHP4 p.Lys809Arg (c.2426A>G)?

NPHP4 p.Lys809Arg (c.2426A>G) is associated with NPHP4-related disorder, nephronophthisis 4, Senior-Loken syndrome 4 (ClinVar).

How common is NPHP4 p.Lys809Arg (c.2426A>G) in the general population?

NPHP4 p.Lys809Arg (c.2426A>G) is very rare (popmax 0.0061%, nfe) (gnomAD).

What do computational predictors say about NPHP4 p.Lys809Arg (c.2426A>G)?

AlphaMissense predicts likely benign (score 0.08) — an in-silico prediction, not a clinical call.

NPHP4 p.Lys809Arg

c.2426A>G · rs747951355 · VCV1514603

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.08 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0061%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

NPHP4-related disorder

Computational evidence

Protein change
AlphaMissense	0.08	likely benign
REVEL	0.1	moderately benign-leaning
SaProt	LLR -5.41	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 0.57	GERP 0.023, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 123 kb · p 0.49 · regional, not allelic
Overall
CADD	14.15	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 0.0061% European (non-Finnish) · 72/1,179,880 alleles

Filtering AF 0.00495% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00455%

Overall 0.00477% 77/1,613,486 alleles · very rare exomes 74/1,461,254 · genomes 3/152,232 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0061%	16,387
Remaining individualsnot grpmax-eligible	0.0032%	31,229
African / African-American	0.00267%	37,476
Admixed American	0.00167%	60,004

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.Lys809Arg
Coding: c.2426A>G
MANE Select: NM_015102
dbSNP: rs747951355
Type: single nucleotide variant
Location: chr1:5887345 (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

Also linked: nephronophthisis 4 Senior-Loken syndrome 4 nephronophthisis

Similar variants

NPHP4 p.Lys809Glu Uncertain significance ★★ ⚠ same residue
NPHP4 p.Lys809Met Uncertain significance ★ ⚠ same residue
NPHP4 p.Lys809Thr Uncertain significance ★ ⚠ 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

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-lys809arg (accessed [today's date]).

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