Is NPHP4 p.Pro1049Ser (c.3145C>T) pathogenic?

NPHP4 p.Pro1049Ser (c.3145C>T) is classified Benign in NPHP4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-02-06). AlphaMissense: ambiguous (0.3679); Rare (popmax 0.167%, sas); Associated with nephronophthisis.

What condition is associated with NPHP4 p.Pro1049Ser (c.3145C>T)?

NPHP4 p.Pro1049Ser (c.3145C>T) is associated with nephronophthisis (ClinVar).

How common is NPHP4 p.Pro1049Ser (c.3145C>T) in the general population?

NPHP4 p.Pro1049Ser (c.3145C>T) is rare (popmax 0.167%, 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.Pro1049Ser (c.3145C>T)?

AlphaMissense predicts ambiguous (score 0.3679) — an in-silico prediction, not a clinical call.

NPHP4 p.Pro1049Ser

c.3145C>T · rs759609852 · VCV1599216

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3679 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.167%, sas)

Conditions

nephronophthisis

Computational evidence

Protein change
AlphaMissense	0.3679	ambiguous
REVEL	0.563	indeterminate
SaProt	LLR -10.74	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.2	GERP 1.9, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 123 kb · p 0.49 · regional, not allelic
Overall
CADD	26.0	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 0.167% South Asian · 149/89,048 alleles

Filtering AF 0.145% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.137%

Overall 0.00934% 150/1,605,504 alleles · rare exomes 147/1,453,160 · genomes 3/152,344 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.167%	598
African / African-American	0.00134%	74,824

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.Pro1049Ser
Coding: c.3145C>T
MANE Select: NM_015102
dbSNP: rs759609852
Type: single nucleotide variant
Location: chr1:5874557 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.44
Residue 1049: 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

For Nephronophthisis (Orphanet):

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

Similar variants

NPHP4 p.Pro1049Leu Uncertain significance ★ ⚠ same residue
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

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-pro1049ser (accessed [today's date]).

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