Is CCDC59 p.Glu189Lys (c.565G>A) pathogenic?

CCDC59 p.Glu189Lys (c.565G>A) is classified Uncertain significance in CCDC59 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-31). AlphaMissense: ambiguous (0.4575); Very rare (popmax 0.00716%, nfe).

How common is CCDC59 p.Glu189Lys (c.565G>A) in the general population?

CCDC59 p.Glu189Lys (c.565G>A) is very rare (popmax 0.00716%, nfe) (gnomAD).

What do computational predictors say about CCDC59 p.Glu189Lys (c.565G>A)?

AlphaMissense predicts ambiguous (score 0.4575) — an in-silico prediction, not a clinical call.

CCDC59 p.Glu189Lys

c.565G>A · rs141837755 · VCV2313487

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4575 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00716%, nfe)

Computational evidence

Protein change
AlphaMissense	0.4575	ambiguous
REVEL	0.578	indeterminate
SaProt	LLR -11.99	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.7, phastCons 1
Regional constraint	o/e 1.27	unconstrained · MANE · 5,222 bp · p 4.2e-06 · regional, not allelic
Overall
CADD	34.0	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 0.00716% European (non-Finnish) · 84/1,173,032 alleles

Filtering AF 0.00591% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00544%

Overall 0.00546% 87/1,592,028 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00716%	13,965
Remaining individualsnot grpmax-eligible	0.00488%	20,494

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: CCDC59
Protein: p.Glu189Lys
Coding: c.565G>A
MANE Select: NM_014167
dbSNP: rs141837755
Type: single nucleotide variant
Location: chr12:82353312 (GRCh38)
Gene constraint: LOEUF 1.185 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.09
Residue 189: the 'disordered' region

Full CCDC59 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCDC59 p.Ala184Val Uncertain significance ★ ⚠ same type
CCDC59 p.Arg109Gly Uncertain significance ★ ⚠ same type
CCDC59 p.Arg11Trp Uncertain significance ★ ⚠ same type
CCDC59 p.Arg50Cys Uncertain significance ★ ⚠ same type
CCDC59 p.Arg5Gly Uncertain significance ★ ⚠ same type
CCDC59 p.Arg6Gly Uncertain significance ★ ⚠ same type
CCDC59 p.Asn216Lys Uncertain significance ★ ⚠ same type
CCDC59 p.Asp131Glu Uncertain significance ★ ⚠ same type

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/ccdc59-p-glu189lys (accessed [today's date]).

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