Is NPHP3 p.Gln131His (c.393G>C) pathogenic?

NPHP3 p.Gln131His (c.393G>C) is classified Uncertain significance in NPHP3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-02-24). AlphaMissense: likely pathogenic (0.7429); Ultra-rare (popmax 0.012%, afr); Associated with renal-hepatic-pancreatic dysplasia 1.

What condition is associated with NPHP3 p.Gln131His (c.393G>C)?

NPHP3 p.Gln131His (c.393G>C) is associated with renal-hepatic-pancreatic dysplasia 1, NPHP3-related Meckel-like syndrome, nephronophthisis 3 (ClinVar).

How common is NPHP3 p.Gln131His (c.393G>C) in the general population?

NPHP3 p.Gln131His (c.393G>C) is ultra-rare (popmax 0.012%, afr) (gnomAD).

What do computational predictors say about NPHP3 p.Gln131His (c.393G>C)?

AlphaMissense predicts likely pathogenic (score 0.7429) — an in-silico prediction, not a clinical call.

NPHP3 p.Gln131His

c.393G>C · rs757835884 · VCV938932

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7429 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.012%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

renal-hepatic-pancreatic dysplasia 1

Computational evidence

Protein change
AlphaMissense	0.7429	likely pathogenic
REVEL	0.502	indeterminate
SaProt	LLR -7.91	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	Δ0.47	donor loss at this position · masked 0 · deltas
Pangolin	Δ0.68	loss · gain 0.11 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.5	GERP 1.5, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 30 kb · p 0.87 · regional, not allelic
Overall
CADD	36.0	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 0.012% African / African-American · 9/74,936 alleles

Filtering AF 0.00623% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00467%

Overall 0.000682% 11/1,612,442 alleles · ultra-rare exomes 2/1,460,208 · genomes 9/152,234 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.012%	8,326
Remaining individualsnot grpmax-eligible	0.0016%	62,440
European (non-Finnish)	8.48e-05%	1,179,838

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.Gln131His
Coding: c.393G>C
MANE Select: NM_153240
dbSNP: rs757835884
Type: single nucleotide variant
Location: chr3:132721963 (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

renal-hepatic-pancreatic dysplasia 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: NPHP3-related Meckel-like syndrome nephronophthisis 3 nephronophthisis

Similar variants

NPHP3 p.Gln131Ter Pathogenic ★ 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-gln131his (accessed [today's date]).

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