Is NPHP1 p.Glu142Asp (c.426G>T) pathogenic?

NPHP1 p.Glu142Asp (c.426G>T) is classified Uncertain significance in NPHP1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-06-07). AlphaMissense: likely benign (0.097); Ultra-rare (popmax 0.0165%, mid); Associated with NPHP1-related disorder.

What condition is associated with NPHP1 p.Glu142Asp (c.426G>T)?

NPHP1 p.Glu142Asp (c.426G>T) is associated with NPHP1-related disorder, nephronophthisis 1, Senior-Loken syndrome 1 (ClinVar).

How common is NPHP1 p.Glu142Asp (c.426G>T) in the general population?

NPHP1 p.Glu142Asp (c.426G>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about NPHP1 p.Glu142Asp (c.426G>T)?

AlphaMissense predicts likely benign (score 0.097) — an in-silico prediction, not a clinical call.

NPHP1 p.Glu142Asp

c.426G>T · rs765568261 · VCV1419832

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.097 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

NPHP1-related disorder

Computational evidence

Protein change
AlphaMissense	0.097	likely benign
REVEL	0.041	moderately benign-leaning
SaProt	LLR -7.98	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 -1.4
Regional constraint	o/e 0.96	unconstrained · MANE · 81 kb · p 0.26 · regional, not allelic
Overall
CADD	7.331	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 0.0165% Middle Eastern · 1/6,058 alleles

Filtering AF 0.00359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00255%

Overall 0.00329% 53/1,609,958 alleles · ultra-rare exomes 48/1,457,916 · genomes 5/152,042 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,058
South Asian	0.00769%	13,000
Remaining individualsnot grpmax-eligible	0.00642%	15,586
European (non-Finnish)	0.00348%	28,697

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.Glu142Asp
Coding: c.426G>T
MANE Select: NM_001128178
dbSNP: rs765568261
Type: single nucleotide variant
Location: chr2:110169902 (GRCh38)
Gene constraint: LOEUF 0.92 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.22 · 2 PDB
Residue 142: the 'disordered' region

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

Disease context

NPHP1-related disorder

Also linked: nephronophthisis 1 Senior-Loken syndrome 1 Joubert syndrome with renal defect nephronophthisis

Similar variants

NPHP1 c.1083+1G>A Likely pathogenic ★★ same condition
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

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-glu142asp (accessed [today's date]).

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