Is NPHP3 p.Arg1255Trp (c.3763C>T) pathogenic?

NPHP3 p.Arg1255Trp (c.3763C>T) is classified Conflicting classifications of pathogenicity in NPHP3 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-04). AlphaMissense: likely benign (0.1037); Very rare (popmax 0.00848%, nfe); Associated with Inborn genetic diseases.

What condition is associated with NPHP3 p.Arg1255Trp (c.3763C>T)?

NPHP3 p.Arg1255Trp (c.3763C>T) is associated with Inborn genetic diseases, renal-hepatic-pancreatic dysplasia 1, NPHP3-related Meckel-like syndrome (ClinVar).

How common is NPHP3 p.Arg1255Trp (c.3763C>T) in the general population?

NPHP3 p.Arg1255Trp (c.3763C>T) is very rare (popmax 0.00848%, nfe) (gnomAD).

What do computational predictors say about NPHP3 p.Arg1255Trp (c.3763C>T)?

AlphaMissense predicts likely benign (score 0.1037) — an in-silico prediction, not a clinical call.

NPHP3 p.Arg1255Trp

c.3763C>T · rs146054765 · VCV219480

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1037 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00848%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1037	likely benign
REVEL	0.529	indeterminate
SaProt	LLR -8.60	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.26 · evaluated, not missing
Constraint at this position
Conservation	phyloP 6.7	GERP 1.2, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 11 kb · p 0.0019 · regional, not allelic
Overall
CADD	22.8	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 0.00848% European (non-Finnish) · 100/1,179,598 alleles

Filtering AF 0.00708% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0066%

Overall 0.00781% 126/1,613,464 alleles · very rare exomes 114/1,461,368 · genomes 12/152,096 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0642%	1,558
European (non-Finnish)grpmax	0.00848%	11,796
Remaining individualsnot grpmax-eligible	0.0064%	15,618
African / African-American	0.00267%	37,440
South Asian	0.0011%	91,076

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg1255Trp
Coding: c.3763C>T
MANE Select: NM_153240
dbSNP: rs146054765
Type: single nucleotide variant
Location: chr3:132682752 (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.Arg1255Gln 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-arg1255trp (accessed [today's date]).

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