Is NPHP1 p.Leu555Val (c.1663C>G) pathogenic?

NPHP1 p.Leu555Val (c.1663C>G) is classified Uncertain significance in NPHP1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-30). AlphaMissense: likely benign (0.2379); Very rare (popmax 0.00415%, nfe); Associated with Inborn genetic diseases.

What condition is associated with NPHP1 p.Leu555Val (c.1663C>G)?

NPHP1 p.Leu555Val (c.1663C>G) is associated with Inborn genetic diseases, nephronophthisis (ClinVar).

How common is NPHP1 p.Leu555Val (c.1663C>G) in the general population?

NPHP1 p.Leu555Val (c.1663C>G) is very rare (popmax 0.00415%, nfe) (gnomAD).

What do computational predictors say about NPHP1 p.Leu555Val (c.1663C>G)?

AlphaMissense predicts likely benign (score 0.2379) — an in-silico prediction, not a clinical call.

NPHP1 p.Leu555Val

c.1663C>G · rs770266229 · VCV1363784

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2379 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00415%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2379	likely benign
REVEL	0.548	indeterminate
SaProt	LLR -7.06	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.99	GERP -0.7, phastCons 0.94
Regional constraint	o/e 0.96	unconstrained · MANE · 81 kb · p 0.26 · regional, not allelic
Overall
CADD	18.2	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 L610V vs ClinVar L555V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00415% European (non-Finnish) · 49/1,179,314 alleles

Filtering AF 0.00318% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00286%

Overall 0.00316% 51/1,613,144 alleles · very rare exomes 49/1,460,942 · genomes 2/152,202 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00415%	24,068
Admixed American	0.00333%	29,993

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.Leu555Val
Coding: c.1663C>G
MANE Select: NM_001128178
dbSNP: rs770266229
Type: single nucleotide variant
Location: chr2:110129239 (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

Also linked: nephronophthisis

Similar variants

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
NPHP1 c.729-2A>G 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-leu555val (accessed [today's date]).

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