Is NPHP3 p.Arg973Ter (c.2917C>T) pathogenic?

NPHP3 p.Arg973Ter (c.2917C>T) is classified Pathogenic in NPHP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-24). Very rare (popmax 0.00267%, afr); Associated with NPHP3-related Meckel-like syndrome.

What condition is associated with NPHP3 p.Arg973Ter (c.2917C>T)?

NPHP3 p.Arg973Ter (c.2917C>T) is associated with NPHP3-related Meckel-like syndrome (ClinVar).

How common is NPHP3 p.Arg973Ter (c.2917C>T) in the general population?

NPHP3 p.Arg973Ter (c.2917C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

NPHP3 p.Arg973Ter

c.2917C>T · rs769291880 · VCV3075695

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Conditions

NPHP3-related Meckel-like syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 21 of 27
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.7	GERP 1.7, phastCons 1
Overall
CADD	43.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/75,014 alleles

Filtering AF 0.000442% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000434% 7/1,614,018 alleles · very rare exomes 7/1,461,824 · genomes 0/152,194 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,507
Admixed American	0.00167%	60,000
European (non-Finnish)	0.000339%	294,990

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.Arg973Ter
Coding: c.2917C>T
MANE Select: NM_153240
dbSNP: rs769291880
Type: single nucleotide variant
Location: chr3:132688858 (GRCh38)
Gene constraint: LOEUF 0.873 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.59 · 1 PDB
Residue 973: a UniProt-annotated variant site (in rhpd1)

Full NPHP3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

NPHP3-related Meckel-like syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

NPHP3 p.Arg973Gly 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-arg973ter (accessed [today's date]).

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