Is NPHP1 p.Val508Ile (c.1522G>A) pathogenic?

NPHP1 p.Val508Ile (c.1522G>A) is classified Conflicting classifications of pathogenicity in NPHP1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-03-03). AlphaMissense: likely benign (0.0664); Very rare (popmax 0.005%, amr); Associated with nephronophthisis.

What condition is associated with NPHP1 p.Val508Ile (c.1522G>A)?

NPHP1 p.Val508Ile (c.1522G>A) is associated with nephronophthisis (ClinVar).

How common is NPHP1 p.Val508Ile (c.1522G>A) in the general population?

NPHP1 p.Val508Ile (c.1522G>A) is very rare (popmax 0.005%, amr) (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.Val508Ile (c.1522G>A)?

AlphaMissense predicts likely benign (score 0.0664) — an in-silico prediction, not a clinical call.

NPHP1 p.Val508Ile

c.1522G>A · rs573192954 · VCV1905125

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0664 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

nephronophthisis

Computational evidence

Protein change
AlphaMissense	0.0664	likely benign
REVEL	0.065	moderately benign-leaning
SaProt	LLR -6.27	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.7	GERP -4.5
Regional constraint	o/e 0.96	unconstrained · MANE · 81 kb · p 0.26 · regional, not allelic
Overall
CADD	0.068	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 V563I vs ClinVar V508I) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.005% Admixed American · 3/60,020 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000683% 11/1,609,992 alleles · very rare exomes 7/1,457,706 · genomes 4/152,286 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	20,007
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,580
Remaining individualsnot grpmax-eligible	0.00321%	31,193
European (non-Finnish)	0.000425%	235,240

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.Val508Ile
Coding: c.1522G>A
MANE Select: NM_001128178
dbSNP: rs573192954
Type: single nucleotide variant
Location: chr2:110143549 (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 — 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 p.Val508Gly Uncertain significance ★★ ⚠ same residue
NPHP1 p.Val508Leu Uncertain significance ★★ ⚠ same residue
NPHP1 p.Val508= Likely benign ★★ same residue
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

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-val508ile (accessed [today's date]).

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