Is NPHP4 p.Thr315= (c.945G>A) pathogenic?

NPHP4 p.Thr315= (c.945G>A) is classified Conflicting classifications of pathogenicity in NPHP4 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-11-23). Rare (popmax 0.347%, afr); Associated with nephronophthisis.

What condition is associated with NPHP4 p.Thr315= (c.945G>A)?

NPHP4 p.Thr315= (c.945G>A) is associated with nephronophthisis (ClinVar).

How common is NPHP4 p.Thr315= (c.945G>A) in the general population?

NPHP4 p.Thr315= (c.945G>A) is rare (popmax 0.347%, afr) (gnomAD).

How is Nephronophthisis inherited?

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

NPHP4 p.Thr315=

c.945G>A · rs115272639 · VCV198869

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

rare (popmax 0.347%, afr)

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 -4.3
Overall
CADD	1.209	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.347% African / African-American · 260/75,030 alleles

Filtering AF 0.312% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.298%

Overall 0.0183% 295/1,613,876 alleles · rare exomes 136/1,461,588 · genomes 159/152,288 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.347%	289
Remaining individualsnot grpmax-eligible	0.0208%	4,807
Admixed American	0.0117%	8,575
South Asian	0.00659%	15,180
Finnishnot grpmax-eligible	0.00156%	63,932
European (non-Finnish)	0.000678%	147,484

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.Thr315=
Coding: c.945G>A
MANE Select: NM_015102
dbSNP: rs115272639
Type: single nucleotide variant
Location: chr1:5948117 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.44
Residue 315: a UniProt-annotated variant site (in)

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.Thr315Met Benign/Likely benign ★★ 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-thr315 (accessed [today's date]).

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