Is NPHP3 p.Phe890Leu (c.2670T>G) pathogenic?

NPHP3 p.Phe890Leu (c.2670T>G) is classified Uncertain significance in NPHP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2017-04-03). AlphaMissense: likely pathogenic (0.7965); Very rare (popmax 0.00267%, afr); Associated with kidney disorder.

What condition is associated with NPHP3 p.Phe890Leu (c.2670T>G)?

NPHP3 p.Phe890Leu (c.2670T>G) is associated with kidney disorder (ClinVar).

How common is NPHP3 p.Phe890Leu (c.2670T>G) in the general population?

NPHP3 p.Phe890Leu (c.2670T>G) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about NPHP3 p.Phe890Leu (c.2670T>G)?

AlphaMissense predicts likely pathogenic (score 0.7965) — an in-silico prediction, not a clinical call.

NPHP3 p.Phe890Leu

c.2670T>G · rs746521044 · VCV1712346

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7965 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

kidney disorder

Computational evidence

Protein change
AlphaMissense	0.7965	likely pathogenic
REVEL	0.196	benign-leaning
SaProt	LLR -4.36	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.32	GERP -3.4, phastCons 0.002
Regional constraint	o/e 0.88	unconstrained · MANE · 11 kb · p 0.0019 · regional, not allelic
Overall
CADD	14.57	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 0.00267% African / African-American · 2/75,038 alleles

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

Overall 0.000186% 3/1,613,678 alleles · very rare exomes 3/1,461,372 · genomes 0/152,306 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,519
Remaining individualsnot grpmax-eligible	0.0016%	62,490

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.Phe890Leu
Coding: c.2670T>G
MANE Select: NM_153240
dbSNP: rs746521044
Type: single nucleotide variant
Location: chr3:132690551 (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

kidney disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

NPHP3 p.Tyr1104Cys Uncertain significance ★★ ⚠ same condition
NPHP3 p.Ala1221= Benign/Likely benign ★★ same condition
NPHP3 p.Ala150Val Benign/Likely benign ★★ same condition
NPHP3 p.Arg1305Cys Benign/Likely benign ★★ same condition
NPHP3 p.Lys1063= Benign/Likely benign ★★ same condition
NPHP3 p.Thr288= Benign/Likely benign ★★ same condition
NPHP3 c.3570+9G>T Conflicting classifications of pathogenicity ★ same condition
NPHP3 c.*108G>A Uncertain significance ★ 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-phe890leu (accessed [today's date]).

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