Is NPHP3 p.Arg1167His (c.3500G>A) pathogenic?

NPHP3 p.Arg1167His (c.3500G>A) is classified Conflicting classifications of pathogenicity in NPHP3 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-01-20). AlphaMissense: likely benign (0.0993); Rare (popmax 0.484%, afr); Associated with kidney disorder.

What condition is associated with NPHP3 p.Arg1167His (c.3500G>A)?

NPHP3 p.Arg1167His (c.3500G>A) is associated with kidney disorder, nephronophthisis (ClinVar).

How common is NPHP3 p.Arg1167His (c.3500G>A) in the general population?

NPHP3 p.Arg1167His (c.3500G>A) is rare (popmax 0.484%, afr) (gnomAD).

What do computational predictors say about NPHP3 p.Arg1167His (c.3500G>A)?

AlphaMissense predicts likely benign (score 0.0993) — an in-silico prediction, not a clinical call.

NPHP3 p.Arg1167His

c.3500G>A · rs111727307 · VCV262705

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0993 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.484%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

kidney disorder

Computational evidence

Protein change
AlphaMissense	0.0993	likely benign
REVEL	0.407	indeterminate
SaProt	LLR -9.81	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP 0.77, phastCons 0.98
Regional constraint	o/e 0.88	unconstrained · MANE · 11 kb · p 0.0019 · regional, not allelic
Overall
CADD	24.4	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 0.484% African / African-American · 363/75,038 alleles

Filtering AF 0.443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.427%

Overall 0.0316% 510/1,613,974 alleles · rare exomes 321/1,461,690 · genomes 189/152,284 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.484%	207
Middle Eastern	0.132%	758
Remaining individualsnot grpmax-eligible	0.114%	880
Admixed American	0.0666%	1,500
South Asian	0.00769%	13,012
East Asian	0.00223%	44,872
European (non-Finnish)	0.0017%	58,995

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: NPHP3
Protein: p.Arg1167His
Coding: c.3500G>A
MANE Select: NM_153240
dbSNP: rs111727307
Type: single nucleotide variant
Location: chr3:132684624 (GRCh38)
Gene constraint: LOEUF 0.873 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.59 · 1 PDB

Full NPHP3 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

Similar variants

NPHP3 c.1985+1G>A Pathogenic/Likely pathogenic ★★ same condition
NPHP3 c.3201+1G>T Likely pathogenic ★★ same condition
NPHP3 c.393+1G>C Likely pathogenic ★★ same condition
NPHP3 c.958-2A>G Pathogenic ★★ same condition
NPHP3 p.Arg1125Ter Pathogenic ★★ same condition
NPHP3 p.Arg1259Ter Pathogenic/Likely pathogenic ★★ same condition
NPHP3 p.Arg142Ter Pathogenic/Likely pathogenic ★★ same condition
NPHP3 p.Arg577Ter 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/nphp3-p-arg1167his (accessed [today's date]).

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