Is ZNF423 p.Pro173= (c.519G>A) pathogenic?

ZNF423 p.Pro173= (c.519G>A) is classified Likely benign in ZNF423 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-01). Ultra-rare (popmax 0.0164%, mid); Associated with nephronophthisis 14.

What condition is associated with ZNF423 p.Pro173= (c.519G>A)?

ZNF423 p.Pro173= (c.519G>A) is associated with nephronophthisis 14 (ClinVar).

How common is ZNF423 p.Pro173= (c.519G>A) in the general population?

ZNF423 p.Pro173= (c.519G>A) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

How is Nephronophthisis inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

ZNF423 p.Pro173=

c.519G>A · rs374152933 · VCV1110186

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Conditions

nephronophthisis 14

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -2.4	GERP -3.9
Overall
CADD	12.18	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00922% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00722%

Overall 0.00582% 94/1,613,922 alleles · ultra-rare exomes 80/1,461,746 · genomes 14/152,176 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
African / African-American	0.016%	6,243
Remaining individualsnot grpmax-eligible	0.0096%	10,414
East Asian	0.00891%	11,221
European (non-Finnish)	0.00593%	16,858
Admixed American	0.00167%	60,012

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: ZNF423
Protein: p.Pro173=
Coding: c.519G>A
MANE Select: NM_001379286
dbSNP: rs374152933
Type: single nucleotide variant
Location: chr16:49638657 (GRCh38)
Gene constraint: LOEUF 0.196 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 61.63 · 1 PDB

Full ZNF423 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

nephronophthisis 14 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Nephronophthisis (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Antenatal, Childhood, Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Finland)

Similar variants

ZNF423 p.Pro173Leu Uncertain significance ★★ ⚠ same residue
ZNF423 c.40+33052G>A Uncertain significance ★★ same condition
ZNF423 p.Ala1075Thr Uncertain significance ★★ ⚠ same condition
ZNF423 p.Ala1101Thr Uncertain significance ★★ ⚠ same condition
ZNF423 p.Ala1108Thr Uncertain significance ★★ ⚠ same condition
ZNF423 p.Ala1291Val Uncertain significance ★★ ⚠ same condition
ZNF423 p.Ala19Val Uncertain significance ★★ ⚠ same condition
ZNF423 p.Ala25Gly 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/znf423-p-pro173 (accessed [today's date]).

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