Is ZNF423 p.Ala487Thr (c.1459G>A) pathogenic?

ZNF423 p.Ala487Thr (c.1459G>A) is classified Uncertain significance in ZNF423 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-07-19). AlphaMissense: likely benign (0.082); Very rare (popmax 0.00754%, nfe); Associated with ciliopathy.

What condition is associated with ZNF423 p.Ala487Thr (c.1459G>A)?

ZNF423 p.Ala487Thr (c.1459G>A) is associated with ciliopathy, nephronophthisis 14 (ClinVar).

How common is ZNF423 p.Ala487Thr (c.1459G>A) in the general population?

ZNF423 p.Ala487Thr (c.1459G>A) is very rare (popmax 0.00754%, nfe) (gnomAD).

What do computational predictors say about ZNF423 p.Ala487Thr (c.1459G>A)?

AlphaMissense predicts likely benign (score 0.082) — an in-silico prediction, not a clinical call.

ZNF423 p.Ala487Thr

c.1459G>A · rs763675078 · VCV1007655

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.082 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00754%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ciliopathy

Computational evidence

Protein change
AlphaMissense	0.082	likely benign
REVEL	0.104	moderately benign-leaning
SaProt	LLR -5.76	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.8	GERP -1, phastCons 0.99
Regional constraint	o/e 0.83	unconstrained · MANE · 1,048 bp · p 0.00028 · regional, not allelic
Overall
CADD	20.5	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM A479T vs ClinVar A487T) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00754% European (non-Finnish) · 89/1,180,050 alleles

Filtering AF 0.00623% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00579%

Overall 0.00582% 94/1,614,036 alleles · very rare exomes 92/1,461,820 · genomes 2/152,216 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00754%	13,259
Remaining individualsnot grpmax-eligible	0.0048%	20,829
Finnishnot grpmax-eligible	0.00156%	63,968
African / African-American	0.00133%	74,940

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.Ala487Thr
Coding: c.1459G>A
MANE Select: NM_001379286
dbSNP: rs763675078
Type: single nucleotide variant
Location: chr16:49637717 (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

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

Also linked: nephronophthisis 14

Similar variants

ZNF423 p.Ala487= Likely benign ★ 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-ala487thr (accessed [today's date]).

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