Is CCDC146 p.Arg589Pro (c.1766G>C) pathogenic?

CCDC146 p.Arg589Pro (c.1766G>C) is classified Uncertain significance in CCDC146 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-28). AlphaMissense: likely pathogenic (0.7954); Very rare (popmax 0.000508%, nfe).

How common is CCDC146 p.Arg589Pro (c.1766G>C) in the general population?

CCDC146 p.Arg589Pro (c.1766G>C) is very rare (popmax 0.000508%, nfe) (gnomAD).

What do computational predictors say about CCDC146 p.Arg589Pro (c.1766G>C)?

AlphaMissense predicts likely pathogenic (score 0.7954) — an in-silico prediction, not a clinical call.

CCDC146 p.Arg589Pro

c.1766G>C · rs202079778 · VCV2621844

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7954 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000508%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7954	likely pathogenic · top 3% in CCDC146
REVEL	0.015	strongly benign-leaning
SaProt	LLR -10.58	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.21 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5.8	GERP 3.5, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 127 kb · p 0.062 · regional, not allelic
Overall
CADD	22.8	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 0.000508% European (non-Finnish) · 6/1,179,980 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000372% 6/1,613,934 alleles · very rare

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: CCDC146
Protein: p.Arg589Pro
Coding: c.1766G>C
MANE Select: NM_020879
dbSNP: rs202079778
Type: single nucleotide variant
Location: chr7:77280500 (GRCh38)
Gene constraint: LOEUF 0.926 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.78
Residue 589: a UniProt-annotated variant site (in spgf94; likely pathogenic)

Full CCDC146 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCDC146 p.Arg589Cys Likely benign ★ ⚠ same residue
CCDC146 c.450-1G>T Likely pathogenic ★ same type
CCDC146 p.Arg306Ter Likely pathogenic ★ same type
CCDC146 p.Arg362Ter Pathogenic ★ same type
CCDC146 p.Ala282Ser Uncertain significance ★ ⚠ same type
CCDC146 p.Ala394Asp Uncertain significance ★ ⚠ same type
CCDC146 p.Ala479Thr Uncertain significance ★ same type
CCDC146 p.Ala560Asp 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/ccdc146-p-arg589pro (accessed [today's date]).

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