Is NPHP1 p.Arg422Leu (c.1265G>T) pathogenic?

NPHP1 p.Arg422Leu (c.1265G>T) is classified Uncertain significance in NPHP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-24). AlphaMissense: ambiguous (0.4785); Very rare (popmax 0.00781%, sas); Associated with nephronophthisis.

What condition is associated with NPHP1 p.Arg422Leu (c.1265G>T)?

NPHP1 p.Arg422Leu (c.1265G>T) is associated with nephronophthisis (ClinVar).

How common is NPHP1 p.Arg422Leu (c.1265G>T) in the general population?

NPHP1 p.Arg422Leu (c.1265G>T) is very rare (popmax 0.00781%, sas) (gnomAD).

How is Nephronophthisis inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about NPHP1 p.Arg422Leu (c.1265G>T)?

AlphaMissense predicts ambiguous (score 0.4785) — an in-silico prediction, not a clinical call.

NPHP1 p.Arg422Leu

c.1265G>T · rs773810185 · VCV955976

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4785 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00781%, sas)

Conditions

nephronophthisis

Computational evidence

Protein change
AlphaMissense	0.4785	ambiguous
REVEL	0.509	indeterminate
SaProt	LLR -5.55	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP 1.5, phastCons 0.52
Regional constraint	o/e 0.96	unconstrained · MANE · 81 kb · p 0.26 · regional, not allelic
Overall
CADD	25.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R477L vs ClinVar R422L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00781% South Asian · 7/89,680 alleles

Filtering AF 0.00364% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00258%

Overall 0.000843% 13/1,542,812 alleles · very rare exomes 13/1,390,716 · genomes 0/152,096 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00781%	12,811
Remaining individualsnot grpmax-eligible	0.00499%	20,047
East Asian	0.00224%	44,544
European (non-Finnish)	0.000179%	557,501

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.Arg422Leu
Coding: c.1265G>T
MANE Select: NM_001128178
dbSNP: rs773810185
Type: single nucleotide variant
Location: chr2:110147920 (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

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

For Nephronophthisis (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Antenatal, Childhood, Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Finland)

Similar variants

NPHP1 p.Arg422Cys Uncertain significance ★ ⚠ same residue
NPHP1 p.Arg422His Uncertain significance ★ ⚠ same residue
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

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-arg422leu (accessed [today's date]).

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