Is NPHP4 p.Asp3Tyr (c.7G>T) pathogenic?

NPHP4 p.Asp3Tyr (c.7G>T) is classified Conflicting classifications of pathogenicity in NPHP4 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-11-19). AlphaMissense: likely benign (0.1663); Ultra-rare (popmax 0.051%, nfe); Associated with nephronophthisis 4.

What condition is associated with NPHP4 p.Asp3Tyr (c.7G>T)?

NPHP4 p.Asp3Tyr (c.7G>T) is associated with nephronophthisis 4, Senior-Loken syndrome 4, nephronophthisis (ClinVar).

How common is NPHP4 p.Asp3Tyr (c.7G>T) in the general population?

NPHP4 p.Asp3Tyr (c.7G>T) is ultra-rare (popmax 0.051%, nfe) (gnomAD).

How is Nephronophthisis inherited?

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

What do computational predictors say about NPHP4 p.Asp3Tyr (c.7G>T)?

AlphaMissense predicts likely benign (score 0.1663) — an in-silico prediction, not a clinical call.

NPHP4 p.Asp3Tyr

c.7G>T · rs145078518 · VCV695555

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1663 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.051%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

nephronophthisis 4

Computational evidence

Protein change
AlphaMissense	0.1663	likely benign
REVEL	0.663	pathogenic-leaning
SaProt	LLR -6.29	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.3	GERP -0.16, phastCons 0.84
Regional constraint	o/e 1.02	unconstrained · MANE · 123 kb · p 0.49 · regional, not allelic
Overall
CADD	21.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.051% European (non-Finnish) · 602/1,179,718 alleles

Filtering AF 0.0476% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0463%

Overall 0.0407% 656/1,613,548 alleles · ultra-rare exomes 589/1,461,282 · genomes 67/152,266 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.051%	1,960
Remaining individualsnot grpmax-eligible	0.0352%	2,840
Finnishnot grpmax-eligible	0.0297%	3,366
Admixed American	0.00667%	14,989
African / African-American	0.00533%	18,751
South Asian	0.0044%	22,745
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,602

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.Asp3Tyr
Coding: c.7G>T
MANE Select: NM_015102
dbSNP: rs145078518
Type: single nucleotide variant
Location: chr1:5986283 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.44
Residue 3: a UniProt-annotated variant site (in slsn4)

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

Disease context

nephronophthisis 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Senior-Loken syndrome 4 nephronophthisis inherited retinal dystrophy

For Nephronophthisis (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Antenatal, Childhood, Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Finland)

Similar variants

NPHP4 p.Asp3Asn Uncertain significance ★★ ⚠ same residue
NPHP4 p.Asp3= 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.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-asp3tyr (accessed [today's date]).

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