Is NPHP3 p.Leu1253Val (c.3757C>G) pathogenic?

NPHP3 p.Leu1253Val (c.3757C>G) is classified Likely pathogenic in NPHP3 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-22). AlphaMissense: likely benign (0.1854); Ultra-rare (popmax 0.0268%, eas); Associated with NPHP3-related Meckel-like syndrome.

What condition is associated with NPHP3 p.Leu1253Val (c.3757C>G)?

NPHP3 p.Leu1253Val (c.3757C>G) is associated with NPHP3-related Meckel-like syndrome, renal-hepatic-pancreatic dysplasia 1, nephronophthisis 3 (ClinVar).

How common is NPHP3 p.Leu1253Val (c.3757C>G) in the general population?

NPHP3 p.Leu1253Val (c.3757C>G) is ultra-rare (popmax 0.0268%, eas) (gnomAD).

What do computational predictors say about NPHP3 p.Leu1253Val (c.3757C>G)?

AlphaMissense predicts likely benign (score 0.1854) — an in-silico prediction, not a clinical call.

NPHP3 p.Leu1253Val

c.3757C>G · rs775281384 · VCV1077017

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1854 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0268%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

NPHP3-related Meckel-like syndrome

Computational evidence

Protein change
AlphaMissense	0.1854	likely benign ⚠ discordant with ClinVar
REVEL	0.452	indeterminate
SaProt	LLR -9.97	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 0.81	GERP -0.71, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 11 kb · p 0.0019 · regional, not allelic
Overall
CADD	19.15	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 0.0268% East Asian · 12/44,854 alleles

Filtering AF 0.0154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0121%

Overall 0.000992% 16/1,613,596 alleles · ultra-rare exomes 16/1,461,396 · genomes 0/152,200 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0268%	3,738
Admixed American	0.00333%	29,997
European (non-Finnish)	0.00017%	589,803

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: NPHP3
Protein: p.Leu1253Val
Coding: c.3757C>G
MANE Select: NM_153240
dbSNP: rs775281384
Type: single nucleotide variant
Location: chr3:132682758 (GRCh38)
Gene constraint: LOEUF 0.873 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.59 · 1 PDB

Full NPHP3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Also linked: renal-hepatic-pancreatic dysplasia 1 nephronophthisis 3 nephronophthisis

Similar variants

NPHP3 p.Leu1253= Benign/Likely benign ★★ same residue
NPHP3 p.Leu1253Met Uncertain significance ★ ⚠ same residue
NPHP3 c.1985+1G>A Pathogenic/Likely pathogenic ★★ same condition
NPHP3 c.3201+1G>T Likely pathogenic ★★ same condition
NPHP3 c.393+1G>C Likely pathogenic ★★ same condition
NPHP3 c.520-1G>T Pathogenic ★★ same condition
NPHP3 c.823+1G>T Likely pathogenic ★★ same condition
NPHP3 c.958-2A>G 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/nphp3-p-leu1253val (accessed [today's date]).

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