Is NPHP4 p.Arg444Gln (c.1331G>A) pathogenic?

NPHP4 p.Arg444Gln (c.1331G>A) is classified Conflicting classifications of pathogenicity in NPHP4 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-06-17). AlphaMissense: likely benign (0.0606); Ultra-rare (popmax 0.0483%, amr); Associated with Inborn genetic diseases.

What condition is associated with NPHP4 p.Arg444Gln (c.1331G>A)?

NPHP4 p.Arg444Gln (c.1331G>A) is associated with Inborn genetic diseases, nephronophthisis 4, Senior-Loken syndrome 4 (ClinVar).

How common is NPHP4 p.Arg444Gln (c.1331G>A) in the general population?

NPHP4 p.Arg444Gln (c.1331G>A) is ultra-rare (popmax 0.0483%, amr) (gnomAD).

What do computational predictors say about NPHP4 p.Arg444Gln (c.1331G>A)?

AlphaMissense predicts likely benign (score 0.0606) — an in-silico prediction, not a clinical call.

NPHP4 p.Arg444Gln

c.1331G>A · rs202179978 · VCV497619

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0606 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0483%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0606	likely benign
REVEL	0.135	moderately benign-leaning
SaProt	LLR -4.47	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.9	GERP -0.15, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 123 kb · p 0.49 · regional, not allelic
Overall
CADD	9.647	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 0.0483% Admixed American · 29/60,000 alleles

Filtering AF 0.0345% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0299%

Overall 0.00446% 72/1,612,940 alleles · ultra-rare exomes 50/1,460,788 · genomes 22/152,152 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0483%	2,069
African / African-American	0.0414%	2,418
Remaining individualsnot grpmax-eligible	0.0032%	31,222
East Asian	0.00223%	44,846
European (non-Finnish)	0.000763%	131,008

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.Arg444Gln
Coding: c.1331G>A
MANE Select: NM_015102
dbSNP: rs202179978
Type: single nucleotide variant
Location: chr1:5927759 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: nephronophthisis 4 Senior-Loken syndrome 4 nephronophthisis

Similar variants

NPHP4 p.Arg444Trp 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
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-arg444gln (accessed [today's date]).

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