Is NPHP3 p.Val1269Met (c.3805G>A) pathogenic?

NPHP3 p.Val1269Met (c.3805G>A) is classified Uncertain significance in NPHP3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-11-27). AlphaMissense: likely benign (0.2716); Very rare (popmax 0.00536%, afr); Associated with renal-hepatic-pancreatic dysplasia 1.

What condition is associated with NPHP3 p.Val1269Met (c.3805G>A)?

NPHP3 p.Val1269Met (c.3805G>A) is associated with renal-hepatic-pancreatic dysplasia 1, NPHP3-related Meckel-like syndrome, nephronophthisis 3 (ClinVar).

How common is NPHP3 p.Val1269Met (c.3805G>A) in the general population?

NPHP3 p.Val1269Met (c.3805G>A) is very rare (popmax 0.00536%, afr) (gnomAD).

What do computational predictors say about NPHP3 p.Val1269Met (c.3805G>A)?

AlphaMissense predicts likely benign (score 0.2716) — an in-silico prediction, not a clinical call.

NPHP3 p.Val1269Met

c.3805G>A · rs150019603 · VCV942300

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2716 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00536%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

renal-hepatic-pancreatic dysplasia 1

Computational evidence

Protein change
AlphaMissense	0.2716	likely benign
REVEL	0.434	indeterminate
SaProt	LLR -7.50	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 2, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 11 kb · p 0.0019 · regional, not allelic
Overall
CADD	25.8	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 0.00536% African / African-American · 4/74,690 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000312% 5/1,601,856 alleles · very rare exomes 3/1,449,680 · genomes 2/152,176 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00536%	18,672
European (non-Finnish)	8.55e-05%	1,169,066

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.Val1269Met
Coding: c.3805G>A
MANE Select: NM_153240
dbSNP: rs150019603
Type: single nucleotide variant
Location: chr3:132682710 (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.Val1269= Likely benign ★ 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-val1269met (accessed [today's date]).

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