Is NPHP1 p.Leu207Val (c.619C>G) pathogenic?

NPHP1 p.Leu207Val (c.619C>G) is classified Uncertain significance in NPHP1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-05-20). AlphaMissense: likely benign (0.1565); Ultra-rare (popmax 0.0577%, afr); Associated with nephronophthisis.

What condition is associated with NPHP1 p.Leu207Val (c.619C>G)?

NPHP1 p.Leu207Val (c.619C>G) is associated with nephronophthisis (ClinVar).

How common is NPHP1 p.Leu207Val (c.619C>G) in the general population?

NPHP1 p.Leu207Val (c.619C>G) is ultra-rare (popmax 0.0577%, afr) (gnomAD).

How is Nephronophthisis inherited?

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

What do computational predictors say about NPHP1 p.Leu207Val (c.619C>G)?

AlphaMissense predicts likely benign (score 0.1565) — an in-silico prediction, not a clinical call.

NPHP1 p.Leu207Val

c.619C>G · rs144088139 · VCV291282

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1565 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0577%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

nephronophthisis

Computational evidence

Protein change
AlphaMissense	0.1565	likely benign
REVEL	0.152	moderately benign-leaning
SaProt	LLR -11.69	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.31	GERP -1.5, phastCons 0.009
Regional constraint	o/e 0.96	unconstrained · MANE · 81 kb · p 0.26 · regional, not allelic
Overall
CADD	13.75	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0577% African / African-American · 43/74,490 alleles

Filtering AF 0.044% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0392%

Overall 0.00281% 45/1,603,848 alleles · ultra-rare exomes 21/1,452,536 · genomes 24/151,312 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0577%	1,732
Remaining individualsnot grpmax-eligible	0.00322%	31,092

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.Leu207Val
Coding: c.619C>G
MANE Select: NM_001128178
dbSNP: rs144088139
Type: single nucleotide variant
Location: chr2:110168457 (GRCh38)
Gene constraint: LOEUF 0.92 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.22 · 2 PDB
Residue 207: the sh3 domain; the 'disordered' region; a β-strand

Full NPHP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

nephronophthisis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Nephronophthisis (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Antenatal, Childhood, Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Finland)

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-leu207val (accessed [today's date]).

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