Is NPHP4 p.Lys424Arg (c.1271A>G) pathogenic?

NPHP4 p.Lys424Arg (c.1271A>G) is classified Uncertain significance in NPHP4 (ClinVar, Single submitter, 3 submitters; last evaluated 2025-05-20). AlphaMissense: likely benign (0.1005); Very rare (popmax 0.00246%, nfe); Associated with Inborn genetic diseases.

What condition is associated with NPHP4 p.Lys424Arg (c.1271A>G)?

NPHP4 p.Lys424Arg (c.1271A>G) is associated with Inborn genetic diseases (ClinVar).

How common is NPHP4 p.Lys424Arg (c.1271A>G) in the general population?

NPHP4 p.Lys424Arg (c.1271A>G) is very rare (popmax 0.00246%, nfe) (gnomAD).

What do computational predictors say about NPHP4 p.Lys424Arg (c.1271A>G)?

AlphaMissense predicts likely benign (score 0.1005) — an in-silico prediction, not a clinical call.

NPHP4 p.Lys424Arg

c.1271A>G · rs537585040 · VCV1284836

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1005 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00246%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1005	likely benign
REVEL	0.323	indeterminate
SaProt	LLR -4.86	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	Δ0.26	donor loss, 1 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 1.8	GERP 0.81, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 123 kb · p 0.49 · regional, not allelic
Overall
CADD	20.3	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 0.00246% European (non-Finnish) · 29/1,177,194 alleles

Filtering AF 0.00173% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00149%

Overall 0.00186% 30/1,610,150 alleles · very rare exomes 28/1,457,976 · genomes 2/152,174 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00246%	40,593
African / African-American	0.00134%	74,794

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.Lys424Arg
Coding: c.1271A>G
MANE Select: NM_015102
dbSNP: rs537585040
Type: single nucleotide variant
Location: chr1:5933178 (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.Lys424Glu Uncertain significance ★ ⚠ same residue
NPHP4 p.Lys424fs Pathogenic/Likely pathogenic ★★ 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

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-lys424arg (accessed [today's date]).

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