Is NPHP4 p.Pro1152Ser (c.3454C>T) pathogenic?

NPHP4 p.Pro1152Ser (c.3454C>T) is classified Conflicting classifications of pathogenicity in NPHP4 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-12-08). AlphaMissense: likely benign (0.1617); Rare (popmax 0.648%, sas); Associated with nephronophthisis.

What condition is associated with NPHP4 p.Pro1152Ser (c.3454C>T)?

NPHP4 p.Pro1152Ser (c.3454C>T) is associated with nephronophthisis, Bardet-Biedl syndrome (ClinVar).

How common is NPHP4 p.Pro1152Ser (c.3454C>T) in the general population?

NPHP4 p.Pro1152Ser (c.3454C>T) is rare (popmax 0.648%, sas) (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 NPHP4 p.Pro1152Ser (c.3454C>T)?

AlphaMissense predicts likely benign (score 0.1617) — an in-silico prediction, not a clinical call.

NPHP4 p.Pro1152Ser

c.3454C>T · rs560329867 · VCV195828

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1617 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.648%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

nephronophthisis

Computational evidence

Protein change
AlphaMissense	0.1617	likely benign
REVEL	0.572	indeterminate
SaProt	LLR -6.53	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 9.6	GERP 1.9, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 123 kb · p 0.49 · regional, not allelic
Overall
CADD	25.9	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 0.648% South Asian · 590/91,084 alleles

Filtering AF 0.604% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.587%

Overall 0.0394% 635/1,610,666 alleles · rare exomes 608/1,458,378 · genomes 27/152,288 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.648%	154
Remaining individualsnot grpmax-eligible	0.056%	1,784
Middle Eastern	0.0165%	6,056
African / African-American	0.00133%	75,030
European (non-Finnish)	0.000678%	147,478

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: NPHP4
Protein: p.Pro1152Ser
Coding: c.3454C>T
MANE Select: NM_015102
dbSNP: rs560329867
Type: single nucleotide variant
Location: chr1:5867758 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.44
Residue 1152: the 'sufficient for basal bodies localization' region

Full NPHP4 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: Bardet-Biedl syndrome

For Nephronophthisis (Orphanet):

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

Similar variants

NPHP4 c.2304+1G>A Pathogenic ★★ same condition
NPHP4 c.2611+1G>A Pathogenic/Likely pathogenic ★★ same condition
NPHP4 c.2611+1G>C Pathogenic ★★ same condition
NPHP4 c.3644+1G>A Pathogenic/Likely pathogenic ★★ same condition
NPHP4 c.3644+1G>T Pathogenic/Likely pathogenic ★★ same condition
NPHP4 c.518-2A>G Likely pathogenic ★★ same condition
NPHP4 c.992+2T>C Likely pathogenic ★★ same condition
NPHP4 p.Arg1109Ter 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/nphp4-p-pro1152ser (accessed [today's date]).

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