Is NPHP4 p.Thr1004= (c.3012G>A) pathogenic?

NPHP4 p.Thr1004= (c.3012G>A) is classified Conflicting classifications of pathogenicity in NPHP4 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-12). Ultra-rare (popmax 0.0133%, amr); Associated with nephronophthisis.

What condition is associated with NPHP4 p.Thr1004= (c.3012G>A)?

NPHP4 p.Thr1004= (c.3012G>A) is associated with nephronophthisis (ClinVar).

How common is NPHP4 p.Thr1004= (c.3012G>A) in the general population?

NPHP4 p.Thr1004= (c.3012G>A) is ultra-rare (popmax 0.0133%, amr) (gnomAD).

How is Nephronophthisis inherited?

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

NPHP4 p.Thr1004=

c.3012G>A · rs185162256 · VCV291268

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 0.0133%, amr)

Conditions

nephronophthisis

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 -20	GERP -3.5
Overall
CADD	0.213	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0133% Admixed American · 8/60,028 alleles

Filtering AF 0.00661% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00482%

Overall 0.00607% 98/1,613,844 alleles · ultra-rare exomes 85/1,461,564 · genomes 13/152,280 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0133%	7,504
East Asian	0.0111%	8,975
African / African-American	0.00933%	10,720
Remaining individualsnot grpmax-eligible	0.008%	12,497
European (non-Finnish)	0.00602%	16,618
South Asian	0.0022%	45,538

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.Thr1004=
Coding: c.3012G>A
MANE Select: NM_015102
dbSNP: rs185162256
Type: single nucleotide variant
Location: chr1:5874906 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.44
Residue 1004: 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.Thr1004Met Uncertain significance ★★ ⚠ same residue
NPHP4 p.Thr1004fs Pathogenic ★★ 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

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-thr1004 (accessed [today's date]).

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