Is CCDC9 p.Arg218Trp (c.652C>T) pathogenic?

CCDC9 p.Arg218Trp (c.652C>T) is classified Uncertain significance in CCDC9 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-15). AlphaMissense: ambiguous (0.5343); Very rare (popmax 0.0056%, sas).

How common is CCDC9 p.Arg218Trp (c.652C>T) in the general population?

CCDC9 p.Arg218Trp (c.652C>T) is very rare (popmax 0.0056%, sas) (gnomAD).

What do computational predictors say about CCDC9 p.Arg218Trp (c.652C>T)?

AlphaMissense predicts ambiguous (score 0.5343) — an in-silico prediction, not a clinical call.

CCDC9 p.Arg218Trp

c.652C>T · rs554313823 · VCV2484997

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5343 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0056%, sas)

Computational evidence

Protein change
AlphaMissense	0.5343	ambiguous
REVEL	0.421	indeterminate
SaProt	LLR -8.18	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.98	GERP 3, phastCons 0.93
Regional constraint	o/e 1.10	unconstrained · MANE · 13 kb · p 0.0052 · regional, not allelic
Overall
CADD	25.2	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 0.0056% South Asian · 4/71,398 alleles

Filtering AF 0.00191% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00108%

Overall 0.00176% 26/1,479,336 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0056%	17,849
Admixed American	0.0026%	38,504
East Asian	0.00235%	42,516
European (non-Finnish)	0.0017%	58,801
African / African-American	0.0014%	71,294

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: CCDC9
Protein: p.Arg218Trp
Coding: c.652C>T
MANE Select: NM_015603
dbSNP: rs554313823
Type: single nucleotide variant
Location: chr19:47264878 (GRCh38)
Gene constraint: LOEUF 1.119 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 59.06
Residue 218: the 'disordered' region

Full CCDC9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCDC9 p.Ala15Val Uncertain significance ★ ⚠ same type
CCDC9 p.Ala175Thr Uncertain significance ★ ⚠ same type
CCDC9 p.Ala322Val Uncertain significance ★ ⚠ same type
CCDC9 p.Ala356Ser Uncertain significance ★ ⚠ same type
CCDC9 p.Ala360Val Uncertain significance ★ ⚠ same type
CCDC9 p.Ala405Val Uncertain significance ★ ⚠ same type
CCDC9 p.Ala455Val Uncertain significance ★ ⚠ same type
CCDC9 p.Ala525Ser 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/ccdc9-p-arg218trp (accessed [today's date]).

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