Is CCDC93 p.Arg474Ile (c.1421G>T) pathogenic?

CCDC93 p.Arg474Ile (c.1421G>T) is classified Uncertain significance in CCDC93 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-09-06). AlphaMissense: ambiguous (0.5573); Very rare (popmax 0.00017%, nfe); Associated with CCDC93-related condition.

What condition is associated with CCDC93 p.Arg474Ile (c.1421G>T)?

CCDC93 p.Arg474Ile (c.1421G>T) is associated with CCDC93-related condition (ClinVar).

How common is CCDC93 p.Arg474Ile (c.1421G>T) in the general population?

CCDC93 p.Arg474Ile (c.1421G>T) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about CCDC93 p.Arg474Ile (c.1421G>T)?

AlphaMissense predicts ambiguous (score 0.5573) — an in-silico prediction, not a clinical call.

CCDC93 p.Arg474Ile

c.1421G>T · VCV3345883

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5573 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Conditions

CCDC93-related condition

Computational evidence

Protein change
AlphaMissense	0.5573	ambiguous
REVEL	0.42	indeterminate
SaProt	LLR -7.63	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.8, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 94 kb · p 0.0042 · regional, not allelic
Overall
CADD	29.1	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 0.00017% European (non-Finnish) · 2/1,179,212 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,460,980 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: CCDC93
Protein: p.Arg474Ile
Coding: c.1421G>T
MANE Select: NM_019044
Type: single nucleotide variant
Location: chr2:117941290 (GRCh38)
Gene constraint: LOEUF 0.986 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.49 · 4 PDB
Residue 474: the 'sufficient for interaction with washc2c' region

Full CCDC93 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

CCDC93-related condition

Similar variants

CCDC93 p.Thr17Ile Likely benign same condition
CCDC93 p.Pro228Leu Benign ★★ same type
CCDC93 p.Ala226Val Uncertain significance ★ ⚠ same type
CCDC93 p.Ala262Thr Uncertain significance ★ ⚠ same type
CCDC93 p.Ala272Thr Uncertain significance ★ ⚠ same type
CCDC93 p.Ala370Thr Uncertain significance ★ ⚠ same type
CCDC93 p.Ala510Thr Uncertain significance ★ ⚠ same type
CCDC93 p.Ala628Val 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/ccdc93-p-arg474ile (accessed [today's date]).

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