Is NPHP4 p.Ala927= (c.2781C>T) pathogenic?

NPHP4 p.Ala927= (c.2781C>T) is classified Conflicting classifications of pathogenicity in NPHP4 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-08-09). Ultra-rare (popmax 0.0508%, mid); Associated with Senior-Loken syndrome 4.

What condition is associated with NPHP4 p.Ala927= (c.2781C>T)?

NPHP4 p.Ala927= (c.2781C>T) is associated with Senior-Loken syndrome 4, nephronophthisis 4, nephronophthisis (ClinVar).

How common is NPHP4 p.Ala927= (c.2781C>T) in the general population?

NPHP4 p.Ala927= (c.2781C>T) is ultra-rare (popmax 0.0508%, mid) (gnomAD).

How is Senior-Loken syndrome inherited?

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

NPHP4 p.Ala927=

c.2781C>T · rs199875603 · VCV695589

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0508%, mid)

Conditions

Senior-Loken syndrome 4

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.26 · evaluated, not missing
Constraint at this position
Conservation	phyloP -4.5	GERP -3.3
Overall
CADD	4.34	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0508% Middle Eastern · 3/5,910 alleles

Filtering AF 0.0138% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00736%

Overall 0.0165% 262/1,587,842 alleles · ultra-rare exomes 241/1,435,638 · genomes 21/152,204 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.415%	241
Remaining individualsnot grpmax-eligible	0.0638%	1,568
Middle Easterngrpmax	0.0508%	1,970
European (non-Finnish)	0.00767%	13,036
South Asian	0.0056%	17,868
Admixed American	0.00506%	19,749
African / African-American	0.00268%	37,257

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala927=
Coding: c.2781C>T
MANE Select: NM_015102
dbSNP: rs199875603
Type: single nucleotide variant
Location: chr1:5877129 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.44
Residue 927: the 'sufficient for basal bodies localization' region; the 'disordered' region

Full NPHP4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Senior-Loken syndrome 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: nephronophthisis 4 nephronophthisis

For Senior-Loken syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood, Infancy
Prevalence: 1-9 / 1 000 000 (Worldwide)

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.517+1G>A 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-ala927 (accessed [today's date]).

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