Is NPHP1 p.Ala570Thr (c.1708G>A) pathogenic?

NPHP1 p.Ala570Thr (c.1708G>A) is classified Uncertain significance in NPHP1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-04-27). AlphaMissense: likely benign (0.1824); Very rare (popmax 0.000764%, nfe); Associated with Senior-Loken syndrome 1.

What condition is associated with NPHP1 p.Ala570Thr (c.1708G>A)?

NPHP1 p.Ala570Thr (c.1708G>A) is associated with Senior-Loken syndrome 1, nephronophthisis 1, Joubert syndrome with renal defect (ClinVar).

How common is NPHP1 p.Ala570Thr (c.1708G>A) in the general population?

NPHP1 p.Ala570Thr (c.1708G>A) is very rare (popmax 0.000764%, nfe) (gnomAD).

How is Senior-Loken syndrome inherited?

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

What do computational predictors say about NPHP1 p.Ala570Thr (c.1708G>A)?

AlphaMissense predicts likely benign (score 0.1824) — an in-silico prediction, not a clinical call.

NPHP1 p.Ala570Thr

c.1708G>A · rs372893275 · VCV1032959

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1824 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000764%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Senior-Loken syndrome 1

Computational evidence

Protein change
AlphaMissense	0.1824	likely benign
REVEL	0.352	indeterminate
SaProt	LLR -6.84	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 2, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 81 kb · p 0.26 · regional, not allelic
Overall
CADD	25.4	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM A625T vs ClinVar A570T) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000764% European (non-Finnish) · 9/1,178,666 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000558% 9/1,612,378 alleles · very rare exomes 9/1,460,098 · genomes 0/152,280 · 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.Ala570Thr
Coding: c.1708G>A
MANE Select: NM_001128178
dbSNP: rs372893275
Type: single nucleotide variant
Location: chr2:110129194 (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

Senior-Loken syndrome 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: nephronophthisis 1 Joubert syndrome with renal defect

For Senior-Loken syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood, Infancy
Prevalence: 1-9 / 1 000 000 (Worldwide)

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-ala570thr (accessed [today's date]).

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