Is NPHP4 p.Pro1204= (c.3612G>A) pathogenic?

NPHP4 p.Pro1204= (c.3612G>A) is classified Conflicting classifications of pathogenicity in NPHP4 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-12-29). Ultra-rare (popmax 0.0661%, mid); Associated with nephronophthisis.

What condition is associated with NPHP4 p.Pro1204= (c.3612G>A)?

NPHP4 p.Pro1204= (c.3612G>A) is associated with nephronophthisis, nephronophthisis 4, Senior-Loken syndrome 4 (ClinVar).

How common is NPHP4 p.Pro1204= (c.3612G>A) in the general population?

NPHP4 p.Pro1204= (c.3612G>A) is ultra-rare (popmax 0.0661%, mid) (gnomAD).

How is Nephronophthisis inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

NPHP4 p.Pro1204=

c.3612G>A · rs374003717 · VCV297793

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0661%, mid)

Conditions

nephronophthisis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -16	GERP -4.1
Overall
CADD	0.424	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0661% Middle Eastern · 4/6,054 alleles

Filtering AF 0.045% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0437%

Overall 0.039% 627/1,609,062 alleles · ultra-rare exomes 572/1,456,756 · genomes 55/152,306 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0661%	1,514
European (non-Finnish)	0.0483%	2,069
Remaining individualsnot grpmax-eligible	0.0369%	2,709
Admixed American	0.0235%	4,255
African / African-American	0.0147%	6,814
Finnishnot grpmax-eligible	0.00628%	15,928
East Asian	0.00224%	44,710
South Asian	0.00111%	89,918

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.Pro1204=
Coding: c.3612G>A
MANE Select: NM_015102
dbSNP: rs374003717
Type: single nucleotide variant
Location: chr1:5866405 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.44
Residue 1204: 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: nephronophthisis 4 Senior-Loken syndrome 4

For Nephronophthisis (Orphanet):

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

Similar variants

NPHP4 p.Pro1204Leu 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.517+1G>A Pathogenic/Likely pathogenic ★★ same condition
NPHP4 c.518-2A>G 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-pro1204 (accessed [today's date]).

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