Is NPHP3 p.Cys229Tyr (c.686G>A) pathogenic?

NPHP3 p.Cys229Tyr (c.686G>A) is classified Uncertain significance in NPHP3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-04-23). AlphaMissense: likely benign (0.1285); Very rare (popmax 0.00333%, amr); Associated with NPHP3-related Meckel-like syndrome.

What condition is associated with NPHP3 p.Cys229Tyr (c.686G>A)?

NPHP3 p.Cys229Tyr (c.686G>A) is associated with NPHP3-related Meckel-like syndrome, renal-hepatic-pancreatic dysplasia 1, nephronophthisis 3 (ClinVar).

How common is NPHP3 p.Cys229Tyr (c.686G>A) in the general population?

NPHP3 p.Cys229Tyr (c.686G>A) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about NPHP3 p.Cys229Tyr (c.686G>A)?

AlphaMissense predicts likely benign (score 0.1285) — an in-silico prediction, not a clinical call.

NPHP3 p.Cys229Tyr

c.686G>A · rs1424177439 · VCV462733

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1285 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

NPHP3-related Meckel-like syndrome

Computational evidence

Protein change
AlphaMissense	0.1285	likely benign
REVEL	0.526	indeterminate
SaProt	LLR -5.70	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP 2, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 30 kb · p 0.87 · regional, not allelic
Overall
CADD	23.8	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 0.00333% Admixed American · 2/60,010 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000186% 3/1,613,944 alleles · very rare exomes 2/1,461,708 · genomes 1/152,236 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,005
European (non-Finnish)	8.47e-05%	1,180,030

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.Cys229Tyr
Coding: c.686G>A
MANE Select: NM_153240
dbSNP: rs1424177439
Type: single nucleotide variant
Location: chr3:132716894 (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

Also linked: renal-hepatic-pancreatic dysplasia 1 nephronophthisis 3 nephronophthisis

Similar variants

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
NPHP3 p.Arg1259Ter Pathogenic/Likely 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-cys229tyr (accessed [today's date]).

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