Is NPHP1 p.Arg48Lys (c.143G>A) pathogenic?

NPHP1 p.Arg48Lys (c.143G>A) is classified Uncertain significance in NPHP1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-02-09). AlphaMissense: likely benign (0.2346); Very rare (popmax 0.00224%, eas); Associated with nephronophthisis 1.

What condition is associated with NPHP1 p.Arg48Lys (c.143G>A)?

NPHP1 p.Arg48Lys (c.143G>A) is associated with nephronophthisis 1, nephronophthisis (ClinVar).

How common is NPHP1 p.Arg48Lys (c.143G>A) in the general population?

NPHP1 p.Arg48Lys (c.143G>A) is very rare (popmax 0.00224%, eas) (gnomAD).

What do computational predictors say about NPHP1 p.Arg48Lys (c.143G>A)?

AlphaMissense predicts likely benign (score 0.2346) — an in-silico prediction, not a clinical call.

NPHP1 p.Arg48Lys

c.143G>A · rs779393628 · VCV1439766

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2346 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00224%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

nephronophthisis 1

Computational evidence

Protein change
AlphaMissense	0.2346	likely benign
REVEL	0.154	moderately benign-leaning
SaProt	LLR -6.21	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.92	donor loss at this position · masked 0 · deltas
Pangolin	Δ0.81	loss · gain 0.02 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.3	GERP 1.7, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 81 kb · p 0.26 · regional, not allelic
Overall
CADD	33.0	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 0.00224% East Asian · 1/44,742 alleles

Overall 0.000125% 2/1,595,770 alleles · very rare exomes 2/1,443,634 · genomes 0/152,136 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00224%	44,742
Remaining individualsnot grpmax-eligible	0.00162%	61,836

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.Arg48Lys
Coding: c.143G>A
MANE Select: NM_001128178
dbSNP: rs779393628
Type: single nucleotide variant
Location: chr2:110201421 (GRCh38)
Gene constraint: LOEUF 0.92 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.22 · 2 PDB
Residue 48: an α-helix

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

Disease context

nephronophthisis 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: nephronophthisis

Similar variants

NPHP1 c.1270-1G>A Pathogenic ★★ same condition
NPHP1 c.1270-2A>G Pathogenic/Likely pathogenic ★★ same condition
NPHP1 c.143+1G>C Likely pathogenic ★★ same condition
NPHP1 c.144-1G>A Pathogenic/Likely pathogenic ★★ same condition
NPHP1 c.1716+1G>T Pathogenic/Likely pathogenic ★★ same condition
NPHP1 c.329+1G>A Pathogenic/Likely pathogenic ★★ same condition
NPHP1 c.522+1G>A Likely pathogenic ★★ same condition
NPHP1 c.729-2A>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/nphp1-p-arg48lys (accessed [today's date]).

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