Is NPHP4 p.Ala940= (c.2820G>A) pathogenic?

NPHP4 p.Ala940= (c.2820G>A) is classified Conflicting classifications of pathogenicity in NPHP4 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-10-12). Rare (popmax 0.258%, afr); Associated with Senior-Loken syndrome 4.

What condition is associated with NPHP4 p.Ala940= (c.2820G>A)?

NPHP4 p.Ala940= (c.2820G>A) is associated with Senior-Loken syndrome 4, nephronophthisis 4, nephronophthisis (ClinVar).

How common is NPHP4 p.Ala940= (c.2820G>A) in the general population?

NPHP4 p.Ala940= (c.2820G>A) is rare (popmax 0.258%, afr) (gnomAD).

How is Senior-Loken syndrome inherited?

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

NPHP4 p.Ala940=

c.2820G>A · rs35575973 · VCV260551

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

rare (popmax 0.258%, afr)

Conditions

Senior-Loken syndrome 4

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.5	GERP -3.2
Overall
CADD	0.35	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.258% African / African-American · 193/74,888 alleles

Filtering AF 0.228% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.216%

Overall 0.017% 272/1,597,544 alleles · rare exomes 161/1,445,226 · genomes 111/152,318 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.258%	388
Admixed American	0.0288%	3,472
East Asian	0.0225%	4,454
Remaining individualsnot grpmax-eligible	0.0209%	4,782
South Asian	0.0089%	11,241
European (non-Finnish)	0.00264%	37,923

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.Ala940=
Coding: c.2820G>A
MANE Select: NM_015102
dbSNP: rs35575973
Type: single nucleotide variant
Location: chr1:5875098 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.44
Residue 940: the 'sufficient for basal bodies localization' region; a UniProt-annotated variant site (sequence variant)

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 p.Ala940Glu Uncertain significance ★ ⚠ same residue
NPHP4 p.Ala940Val Conflicting classifications of pathogenicity ★ ⚠ 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

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-ala940 (accessed [today's date]).

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