Is ZNF469 p.Pro2139= (c.6417T>C) pathogenic?

ZNF469 p.Pro2139= (c.6417T>C) is classified Conflicting classifications of pathogenicity in ZNF469 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-12-21). Ultra-rare (popmax 0.0685%, eas); Associated with Cardiovascular phenotype.

What condition is associated with ZNF469 p.Pro2139= (c.6417T>C)?

ZNF469 p.Pro2139= (c.6417T>C) is associated with Cardiovascular phenotype, Ehlers-Danlos syndrome (ClinVar).

How common is ZNF469 p.Pro2139= (c.6417T>C) in the general population?

ZNF469 p.Pro2139= (c.6417T>C) is ultra-rare (popmax 0.0685%, eas) (gnomAD).

ZNF469 p.Pro2139=

c.6417T>C · rs369067040 · VCV1702142

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0685%, eas)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.69	GERP -2.4
Overall
CADD	1.968	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0685% East Asian · 28/40,864 alleles

Filtering AF 0.0487% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0419%

Overall 0.00194% 30/1,548,652 alleles · ultra-rare exomes 26/1,396,346 · genomes 4/152,306 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0685%	1,459
Remaining individualsnot grpmax-eligible	0.00167%	59,968
South Asian	0.00119%	83,984

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: ZNF469
Protein: p.Pro2139=
Coding: c.6417T>C
MANE Select: NM_001367624
dbSNP: rs369067040
Type: single nucleotide variant
Location: chr16:88433887 (GRCh38)
Gene constraint: LOEUF 1.711 · pLI 0.26 (gnomAD)
Residue 2139: the 'disordered' region

Full ZNF469 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

Also linked: Ehlers-Danlos syndrome

Similar variants

ZNF469 p.Gln2149Ter Pathogenic ★★ same condition
ZNF469 p.Glu176Ter Pathogenic ★★ same condition
ZNF469 p.Ala1001Asp Uncertain significance ★★ ⚠ same condition
ZNF469 p.Ala1001Val Uncertain significance ★★ ⚠ same condition
ZNF469 p.Ala1006Thr Uncertain significance ★★ ⚠ same condition
ZNF469 p.Ala1095Thr Uncertain significance ★★ ⚠ same condition
ZNF469 p.Ala1251Thr Uncertain significance ★★ ⚠ same condition
ZNF469 p.Ala1329Thr 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/znf469-p-pro2139 (accessed [today's date]).

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