Is NPHP3 p.Ser1252Arg (c.3756C>G) pathogenic?

NPHP3 p.Ser1252Arg (c.3756C>G) is classified Conflicting classifications of pathogenicity in NPHP3 (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2026-02-01). AlphaMissense: likely pathogenic (0.8228); Rare (popmax 0.114%, nfe); Associated with nephronophthisis.

What condition is associated with NPHP3 p.Ser1252Arg (c.3756C>G)?

NPHP3 p.Ser1252Arg (c.3756C>G) is associated with nephronophthisis, renal-hepatic-pancreatic dysplasia 1, NPHP3-related Meckel-like syndrome (ClinVar).

How common is NPHP3 p.Ser1252Arg (c.3756C>G) in the general population?

NPHP3 p.Ser1252Arg (c.3756C>G) is rare (popmax 0.114%, nfe) (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 NPHP3 p.Ser1252Arg (c.3756C>G)?

AlphaMissense predicts likely pathogenic (score 0.8228) — an in-silico prediction, not a clinical call.

NPHP3 p.Ser1252Arg

c.3756C>G · rs143451766 · VCV195996

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

AlphaMissense

likely pathogenic

0.8228 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.114%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

nephronophthisis

Computational evidence

Protein change
AlphaMissense	0.8228	likely pathogenic
REVEL	0.605	indeterminate
SaProt	LLR -9.23	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP -0.7, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 11 kb · p 0.0019 · regional, not allelic
Overall
CADD	23.7	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 0.114% European (non-Finnish) · 1,349/1,179,558 alleles

Filtering AF 0.109% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.107%

Overall 0.0911% 1,470/1,613,506 alleles · rare exomes 1,373/1,461,338 · genomes 97/152,168 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.114%	874
Middle Eastern	0.066%	1,515
South Asian	0.0593%	1,686
Remaining individualsnot grpmax-eligible	0.0432%	2,315
Admixed American	0.0233%	4,286
African / African-American	0.0187%	5,356
Finnishnot grpmax-eligible	0.0125%	7,999

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.Ser1252Arg
Coding: c.3756C>G
MANE Select: NM_153240
dbSNP: rs143451766
Type: single nucleotide variant
Location: chr3:132682759 (GRCh38)
Gene constraint: LOEUF 0.873 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.59 · 1 PDB
Residue 1252: a UniProt-annotated variant site (in nphp3)

Full NPHP3 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

Also linked: renal-hepatic-pancreatic dysplasia 1 NPHP3-related Meckel-like syndrome nephronophthisis 3

For Nephronophthisis (Orphanet):

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

Similar variants

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
NPHP3 p.Arg1125Ter Pathogenic ★★ same condition
NPHP3 p.Arg1259Ter 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/nphp3-p-ser1252arg (accessed [today's date]).

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