Is NPHP1 p.Ser424Pro (c.1270T>C) pathogenic?

NPHP1 p.Ser424Pro (c.1270T>C) is classified Uncertain significance in NPHP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-27). AlphaMissense: ambiguous (0.3709); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with NPHP1 p.Ser424Pro (c.1270T>C)?

NPHP1 p.Ser424Pro (c.1270T>C) is associated with Inborn genetic diseases (ClinVar).

How common is NPHP1 p.Ser424Pro (c.1270T>C) in the general population?

NPHP1 p.Ser424Pro (c.1270T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about NPHP1 p.Ser424Pro (c.1270T>C)?

AlphaMissense predicts ambiguous (score 0.3709) — an in-silico prediction, not a clinical call.

NPHP1 p.Ser424Pro

c.1270T>C · rs2467252205 · VCV2297805

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3709 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3709	ambiguous
REVEL	0.218	benign-leaning
SaProt	LLR -9.51	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.1	GERP 1.8, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 81 kb · p 0.26 · regional, not allelic
Overall
CADD	27.3	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 S479P vs ClinVar S424P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: NPHP1
Protein: p.Ser424Pro
Coding: c.1270T>C
MANE Select: NM_001128178
dbSNP: rs2467252205
Type: single nucleotide variant
Location: chr2:110146835 (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.Ser424Ter Likely pathogenic ★ 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-ser424pro (accessed [today's date]).

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