Is NPHP4 p.Gly754Arg (c.2260G>A) pathogenic?

NPHP4 p.Gly754Arg (c.2260G>A) is classified Conflicting classifications of pathogenicity in NPHP4 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-11-03). AlphaMissense: likely pathogenic (0.9284); Very rare (popmax 0.00935%, afr); Associated with NPHP4-related disorder.

What condition is associated with NPHP4 p.Gly754Arg (c.2260G>A)?

NPHP4 p.Gly754Arg (c.2260G>A) is associated with NPHP4-related disorder, Senior-Loken syndrome 4, nephronophthisis (ClinVar).

How common is NPHP4 p.Gly754Arg (c.2260G>A) in the general population?

NPHP4 p.Gly754Arg (c.2260G>A) is very rare (popmax 0.00935%, afr) (gnomAD).

What do computational predictors say about NPHP4 p.Gly754Arg (c.2260G>A)?

AlphaMissense predicts likely pathogenic (score 0.9284) — an in-silico prediction, not a clinical call.

NPHP4 p.Gly754Arg

c.2260G>A · rs373962831 · VCV297808

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9284 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00935%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

NPHP4-related disorder

Computational evidence

Protein change
AlphaMissense	0.9284	likely pathogenic · top 5% in NPHP4
REVEL	0.753	pathogenic-leaning
SaProt	LLR -9.40	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
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	24.7	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 0.00935% African / African-American · 7/74,830 alleles

Filtering AF 0.00438% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00309%

Overall 0.00161% 26/1,609,964 alleles · very rare exomes 22/1,457,806 · genomes 4/152,158 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00935%	10,690
Remaining individualsnot grpmax-eligible	0.00482%	20,765
South Asian	0.00442%	22,601
Finnishnot grpmax-eligible	0.00158%	63,478
European (non-Finnish)	0.000934%	107,089

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.Gly754Arg
Coding: c.2260G>A
MANE Select: NM_015102
dbSNP: rs373962831
Type: single nucleotide variant
Location: chr1:5890912 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.44
Residue 754: a UniProt-annotated variant site (in nphp4; affects interaction with rpgrip1l; disrupts interaction with rpgrip1)

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

Disease context

Also linked: Senior-Loken syndrome 4 nephronophthisis

Similar variants

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
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-gly754arg (accessed [today's date]).

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