Is NPHP3 p.Arg705His (c.2114G>A) pathogenic?

NPHP3 p.Arg705His (c.2114G>A) is classified Uncertain significance in NPHP3 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-06-24). AlphaMissense: likely benign (0.1391); Ultra-rare (popmax 0.0133%, amr); Associated with Inborn genetic diseases.

What condition is associated with NPHP3 p.Arg705His (c.2114G>A)?

NPHP3 p.Arg705His (c.2114G>A) is associated with Inborn genetic diseases, renal-hepatic-pancreatic dysplasia 1, NPHP3-related Meckel-like syndrome (ClinVar).

How common is NPHP3 p.Arg705His (c.2114G>A) in the general population?

NPHP3 p.Arg705His (c.2114G>A) is ultra-rare (popmax 0.0133%, amr) (gnomAD).

What do computational predictors say about NPHP3 p.Arg705His (c.2114G>A)?

AlphaMissense predicts likely benign (score 0.1391) — an in-silico prediction, not a clinical call.

NPHP3 p.Arg705His

c.2114G>A · rs139548649 · VCV499828

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1391 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1391	likely benign
REVEL	0.295	indeterminate
SaProt	LLR -5.31	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.3	GERP 0.99, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 30 kb · p 0.87 · regional, not allelic
Overall
CADD	23.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0133% Admixed American · 8/60,034 alleles

Filtering AF 0.00661% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00482%

Overall 0.00477% 77/1,614,070 alleles · ultra-rare exomes 74/1,461,764 · genomes 3/152,306 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0133%	7,504
East Asian	0.00891%	11,219
South Asian	0.00769%	13,012
European (non-Finnish)	0.00458%	21,851
Remaining individualsnot grpmax-eligible	0.0032%	31,253
Finnishnot grpmax-eligible	0.00156%	64,010
African / African-American	0.00133%	75,040

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.Arg705His
Coding: c.2114G>A
MANE Select: NM_153240
dbSNP: rs139548649
Type: single nucleotide variant
Location: chr3:132696788 (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

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

Also linked: renal-hepatic-pancreatic dysplasia 1 NPHP3-related Meckel-like syndrome nephronophthisis 3 nephronophthisis

Similar variants

NPHP3 p.Arg705Gly Uncertain significance ★ ⚠ same residue
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.520-1G>T Pathogenic ★★ same condition
NPHP3 c.823+1G>T Likely pathogenic ★★ same condition
NPHP3 c.958-2A>G Pathogenic ★★ same condition
NPHP3 p.Arg1125Ter 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-arg705his (accessed [today's date]).

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