Is NPHP4 p.Asp753Asn (c.2257G>A) pathogenic?

NPHP4 p.Asp753Asn (c.2257G>A) is classified Conflicting classifications of pathogenicity in NPHP4 (ClinVar, Conflicting submitters, 12 submitters; last evaluated 2026-01-22). AlphaMissense: ambiguous (0.3677); Low-frequency (popmax 1.07%, afr); Associated with kidney disorder.

What condition is associated with NPHP4 p.Asp753Asn (c.2257G>A)?

NPHP4 p.Asp753Asn (c.2257G>A) is associated with kidney disorder, nephronophthisis 4, Senior-Loken syndrome 4 (ClinVar).

How common is NPHP4 p.Asp753Asn (c.2257G>A) in the general population?

NPHP4 p.Asp753Asn (c.2257G>A) is low-frequency (popmax 1.07%, afr) (gnomAD).

What do computational predictors say about NPHP4 p.Asp753Asn (c.2257G>A)?

AlphaMissense predicts ambiguous (score 0.3677) — an in-silico prediction, not a clinical call.

NPHP4 p.Asp753Asn

c.2257G>A · rs148424288 · VCV194764

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 12 submitters

AlphaMissense

ambiguous

0.3677 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.07%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

kidney disorder

Computational evidence

Protein change
AlphaMissense	0.3677	ambiguous
REVEL	0.82	moderately pathogenic-leaning
SaProt	LLR -9.77	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 2, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 123 kb · p 0.49 · regional, not allelic
Overall
CADD	24.0	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 1.07% African / African-American · 805/74,980 alleles

Filtering AF 1.01% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.988%

Overall 0.0572% 921/1,610,448 alleles · low-frequency exomes 468/1,458,140 · genomes 453/152,308 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.07%	93
Remaining individualsnot grpmax-eligible	0.061%	1,640
Admixed American	0.0569%	1,757
Middle Eastern	0.0496%	2,017
European (non-Finnish)	0.0034%	29,453
South Asian	0.00111%	90,484

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.Asp753Asn
Coding: c.2257G>A
MANE Select: NM_015102
dbSNP: rs148424288
Type: single nucleotide variant
Location: chr1:5890915 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.44

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

Disease context

kidney disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: nephronophthisis 4 Senior-Loken syndrome 4 nephronophthisis

Similar variants

NPHP4 p.Asp753= 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
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-asp753asn (accessed [today's date]).

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