Is NPHP1 p.Arg402Ser (c.1206G>T) pathogenic?

NPHP1 p.Arg402Ser (c.1206G>T) is classified Likely benign in NPHP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-01). AlphaMissense: likely pathogenic (0.9534); Ultra-rare (popmax 0.0357%, eas); Associated with Inborn genetic diseases.

What condition is associated with NPHP1 p.Arg402Ser (c.1206G>T)?

NPHP1 p.Arg402Ser (c.1206G>T) is associated with Inborn genetic diseases (ClinVar).

How common is NPHP1 p.Arg402Ser (c.1206G>T) in the general population?

NPHP1 p.Arg402Ser (c.1206G>T) is ultra-rare (popmax 0.0357%, eas) (gnomAD).

What do computational predictors say about NPHP1 p.Arg402Ser (c.1206G>T)?

AlphaMissense predicts likely pathogenic (score 0.9534) — an in-silico prediction, not a clinical call.

NPHP1 p.Arg402Ser

c.1206G>T · VCV3407369

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9534 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0357%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9534	likely pathogenic · top 2% in NPHP1
REVEL	0.724	pathogenic-leaning
SaProt	LLR -13.07	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -1.5	GERP -0.38
Regional constraint	o/e 0.96	unconstrained · MANE · 81 kb · p 0.26 · regional, not allelic
Overall
CADD	21.8	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 R457S vs ClinVar R402S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0357% East Asian · 16/44,866 alleles

Filtering AF 0.0223% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0182%

Overall 0.000993% 16/1,611,582 alleles · ultra-rare exomes 14/1,459,538 · genomes 2/152,044 · joint denominator

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.Arg402Ser
Coding: c.1206G>T
MANE Select: NM_001128178
Type: single nucleotide variant
Location: chr2:110147979 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

NPHP1 p.Arg402= Likely benign ★ same residue
NPHP1 p.Gly287Arg Pathogenic ★★ same condition
NPHP1 c.771+136C>A Uncertain significance ★★ ⚠ same condition
NPHP1 c.771+26A>G Uncertain significance ★★ ⚠ same condition
NPHP1 c.771+38G>T Uncertain significance ★★ ⚠ same condition
NPHP1 p.Arg389His Uncertain significance ★★ ⚠ same condition
NPHP1 p.Arg628Gln Uncertain significance ★★ ⚠ same condition
NPHP1 p.Asn59His 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-arg402ser (accessed [today's date]).

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