Is NPHP1 p.Arg588Lys (c.1763G>A) pathogenic?

NPHP1 p.Arg588Lys (c.1763G>A) is classified Uncertain significance in NPHP1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-07-15). AlphaMissense: likely benign (0.124); Ultra-rare (popmax 0.0253%, sas); Associated with NPHP1-related disorder.

What condition is associated with NPHP1 p.Arg588Lys (c.1763G>A)?

NPHP1 p.Arg588Lys (c.1763G>A) is associated with NPHP1-related disorder (ClinVar).

How common is NPHP1 p.Arg588Lys (c.1763G>A) in the general population?

NPHP1 p.Arg588Lys (c.1763G>A) is ultra-rare (popmax 0.0253%, sas) (gnomAD).

What do computational predictors say about NPHP1 p.Arg588Lys (c.1763G>A)?

AlphaMissense predicts likely benign (score 0.124) — an in-silico prediction, not a clinical call.

NPHP1 p.Arg588Lys

c.1763G>A · VCV3354387

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.124 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0253%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

NPHP1-related disorder

Computational evidence

Protein change
AlphaMissense	0.124	likely benign
REVEL	0.091	moderately benign-leaning
SaProt	LLR -4.51	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.42 · evaluated, not missing
Pangolin	Δ0.20	gain · loss 0.02 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 2.6	GERP 0.9, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 81 kb · p 0.26 · regional, not allelic
Overall
CADD	23.8	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R643K vs ClinVar R588K) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0253% South Asian · 23/91,072 alleles

Filtering AF 0.0172% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0146%

Overall 0.00155% 25/1,614,056 alleles · ultra-rare exomes 25/1,461,778 · genomes 0/152,278 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0253%	3,960
Remaining individualsnot grpmax-eligible	0.0016%	62,496
African / African-American	0.00133%	75,048

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: NPHP1
Protein: p.Arg588Lys
Coding: c.1763G>A
MANE Select: NM_001128178
Type: single nucleotide variant
Location: chr2:110124062 (GRCh38)
Gene constraint: LOEUF 0.92 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.22 · 2 PDB

Full NPHP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

NPHP1-related disorder

Similar variants

NPHP1 p.Arg588= Likely benign ★ same residue
NPHP1 c.1270-1G>A Pathogenic ★★ same condition
NPHP1 c.1716+1G>T Pathogenic/Likely pathogenic ★★ same condition
NPHP1 c.771+58C>T Pathogenic/Likely pathogenic ★★ same condition
NPHP1 p.Trp575Ter Likely pathogenic ★★ same condition
NPHP1 p.Tyr294Ter Pathogenic/Likely pathogenic ★★ same condition
NPHP1 p.Glu142Asp Uncertain significance ★★ ⚠ same condition
NPHP1 c.771+41A>G 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/nphp1-p-arg588lys (accessed [today's date]).

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