Is NPHP4 p.Arg1054His (c.3161G>A) pathogenic?

NPHP4 p.Arg1054His (c.3161G>A) is classified Uncertain significance in NPHP4 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-12-19). AlphaMissense: likely benign (0.2054); Ultra-rare (popmax 0.0643%, afr); Associated with nephronophthisis.

What condition is associated with NPHP4 p.Arg1054His (c.3161G>A)?

NPHP4 p.Arg1054His (c.3161G>A) is associated with nephronophthisis, nephronophthisis 4, Senior-Loken syndrome 4 (ClinVar).

How common is NPHP4 p.Arg1054His (c.3161G>A) in the general population?

NPHP4 p.Arg1054His (c.3161G>A) is ultra-rare (popmax 0.0643%, afr) (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.Arg1054His (c.3161G>A)?

AlphaMissense predicts likely benign (score 0.2054) — an in-silico prediction, not a clinical call.

NPHP4 p.Arg1054His

c.3161G>A · rs369950850 · VCV578586

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.2054 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0643%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

nephronophthisis

Computational evidence

Protein change
AlphaMissense	0.2054	likely benign
REVEL	0.73	pathogenic-leaning
SaProt	LLR -8.58	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 7.5	GERP 1.9, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 123 kb · p 0.49 · regional, not allelic
Overall
CADD	29.8	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 0.0643% African / African-American · 48/74,644 alleles

Filtering AF 0.0497% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0446%

Overall 0.0145% 232/1,599,360 alleles · ultra-rare exomes 180/1,447,108 · genomes 52/152,252 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0643%	1,555
Finnishnot grpmax-eligible	0.0513%	1,951
East Asian	0.0407%	2,456
Admixed American	0.0395%	2,530
South Asian	0.0249%	4,011
Middle Eastern	0.0166%	6,024
Remaining individualsnot grpmax-eligible	0.0145%	6,878
European (non-Finnish)	0.00673%	14,857

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.Arg1054His
Coding: c.3161G>A
MANE Select: NM_015102
dbSNP: rs369950850
Type: single nucleotide variant
Location: chr1:5874541 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.44
Residue 1054: 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

Also linked: nephronophthisis 4 Senior-Loken syndrome 4

For Nephronophthisis (Orphanet):

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

Similar variants

NPHP4 p.Arg1054Cys 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-arg1054his (accessed [today's date]).

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