Is NPHP1 p.Ser574Leu (c.1721C>T) pathogenic?

NPHP1 p.Ser574Leu (c.1721C>T) is classified Uncertain significance in NPHP1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-02-09). AlphaMissense: likely benign (0.0856); Ultra-rare (popmax 0.0421%, nfe); Associated with nephronophthisis 1.

What condition is associated with NPHP1 p.Ser574Leu (c.1721C>T)?

NPHP1 p.Ser574Leu (c.1721C>T) is associated with nephronophthisis 1, Senior-Loken syndrome 1, Joubert syndrome with renal defect (ClinVar).

How common is NPHP1 p.Ser574Leu (c.1721C>T) in the general population?

NPHP1 p.Ser574Leu (c.1721C>T) is ultra-rare (popmax 0.0421%, nfe) (gnomAD).

What do computational predictors say about NPHP1 p.Ser574Leu (c.1721C>T)?

AlphaMissense predicts likely benign (score 0.0856) — an in-silico prediction, not a clinical call.

NPHP1 p.Ser574Leu

c.1721C>T · rs138181219 · VCV330728

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0856 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0421%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

nephronophthisis 1

Computational evidence

Protein change
AlphaMissense	0.0856	likely benign
REVEL	0.092	moderately benign-leaning
SaProt	LLR -5.74	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.47 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.4	GERP 0.49, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 81 kb · p 0.26 · regional, not allelic
Overall
CADD	25.1	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 S629L vs ClinVar S574L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0421% European (non-Finnish) · 497/1,179,136 alleles

Filtering AF 0.039% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0379%

Overall 0.0342% 552/1,612,702 alleles · ultra-rare exomes 525/1,460,566 · genomes 27/152,136 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.122%	822
European (non-Finnish)grpmax	0.0421%	2,373
Remaining individualsnot grpmax-eligible	0.0224%	4,463
East Asian	0.00446%	22,424
Admixed American	0.00167%	59,998
Finnishnot grpmax-eligible	0.00157%	63,646
African / African-American	0.00133%	74,988

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser574Leu
Coding: c.1721C>T
MANE Select: NM_001128178
dbSNP: rs138181219
Type: single nucleotide variant
Location: chr2:110125677 (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 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

Similar variants

NPHP1 p.Ser574= Likely benign ★★ same residue
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

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-ser574leu (accessed [today's date]).

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