Is NPHP4 p.Val1381= (c.4143C>T) pathogenic?

NPHP4 p.Val1381= (c.4143C>T) is classified Conflicting classifications of pathogenicity in NPHP4 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-12-23). Ultra-rare (popmax 0.024%, amr); Associated with nephronophthisis.

What condition is associated with NPHP4 p.Val1381= (c.4143C>T)?

NPHP4 p.Val1381= (c.4143C>T) is associated with nephronophthisis (ClinVar).

How common is NPHP4 p.Val1381= (c.4143C>T) in the general population?

NPHP4 p.Val1381= (c.4143C>T) is ultra-rare (popmax 0.024%, amr) (gnomAD).

How is Nephronophthisis inherited?

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

NPHP4 p.Val1381=

c.4143C>T · rs766613810 · VCV288025

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.024%, amr)

Conditions

nephronophthisis

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>T here scores Δ0.45 · evaluated, not missing
Constraint at this position
Conservation	phyloP -9.1	GERP -3.6
Overall
CADD	0.02	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.024% Admixed American · 14/58,258 alleles

Filtering AF 0.0145% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0116%

Overall 0.00151% 24/1,593,878 alleles · ultra-rare exomes 22/1,446,376 · genomes 2/147,502 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.024%	4,161
Remaining individualsnot grpmax-eligible	0.00324%	30,828
East Asian	0.00226%	44,322
African / African-American	0.00137%	72,988
South Asian	0.00113%	88,568
European (non-Finnish)	0.000428%	233,673

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.Val1381=
Coding: c.4143C>T
MANE Select: NM_015102
dbSNP: rs766613810
Type: single nucleotide variant
Location: chr1:5863403 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.44
Residue 1381: 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.Val1381Ile 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.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-val1381 (accessed [today's date]).

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