Is NPHP4 p.Arg906His (c.2717G>A) pathogenic?

NPHP4 p.Arg906His (c.2717G>A) is classified Conflicting classifications of pathogenicity in NPHP4 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-12-28). AlphaMissense: likely benign (0.0791); Rare (popmax 0.598%, eas); Associated with nephronophthisis 4.

What condition is associated with NPHP4 p.Arg906His (c.2717G>A)?

NPHP4 p.Arg906His (c.2717G>A) is associated with nephronophthisis 4, Senior-Loken syndrome 4, nephronophthisis (ClinVar).

How common is NPHP4 p.Arg906His (c.2717G>A) in the general population?

NPHP4 p.Arg906His (c.2717G>A) is rare (popmax 0.598%, eas) (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.Arg906His (c.2717G>A)?

AlphaMissense predicts likely benign (score 0.0791) — an in-silico prediction, not a clinical call.

NPHP4 p.Arg906His

c.2717G>A · rs77973802 · VCV1161892

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0791 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.598%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

nephronophthisis 4

Computational evidence

Protein change
AlphaMissense	0.0791	likely benign
REVEL	0.137	moderately benign-leaning
SaProt	LLR -7.54	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -5.7	GERP -2
Regional constraint	o/e 1.02	unconstrained · MANE · 123 kb · p 0.49 · regional, not allelic
Overall
CADD	1.235	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 0.598% East Asian · 266/44,458 alleles

Filtering AF 0.539% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.516%

Overall 0.0186% 299/1,604,260 alleles · rare exomes 274/1,451,868 · genomes 25/152,392 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.598%	167
African / African-American	0.0227%	4,407
Remaining individualsnot grpmax-eligible	0.00967%	10,339
Admixed American	0.00169%	59,014
South Asian	0.00112%	89,498
European (non-Finnish)	0.000681%	146,864

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.Arg906His
Coding: c.2717G>A
MANE Select: NM_015102
dbSNP: rs77973802
Type: single nucleotide variant
Location: chr1:5877193 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.44
Residue 906: the 'sufficient for basal bodies localization' region; the 'disordered' region; a UniProt-annotated variant site (found in a patient with cardiac laterality defects; uncertain significance)

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

For Nephronophthisis (Orphanet):

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

Similar variants

NPHP4 p.Arg906= Conflicting classifications of pathogenicity ★ same residue
NPHP4 p.Arg906Cys 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

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-arg906his (accessed [today's date]).

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