Is CCDC93 p.Leu469Ser (c.1406T>C) pathogenic?

CCDC93 p.Leu469Ser (c.1406T>C) is classified Uncertain significance in CCDC93 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-18). AlphaMissense: ambiguous (0.4972); Very rare (popmax 0.00034%, nfe).

How common is CCDC93 p.Leu469Ser (c.1406T>C) in the general population?

CCDC93 p.Leu469Ser (c.1406T>C) is very rare (popmax 0.00034%, nfe) (gnomAD).

What do computational predictors say about CCDC93 p.Leu469Ser (c.1406T>C)?

AlphaMissense predicts ambiguous (score 0.4972) — an in-silico prediction, not a clinical call.

CCDC93 p.Leu469Ser

c.1406T>C · VCV3828952

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4972 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00034%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4972	ambiguous
REVEL	0.28	benign-leaning
SaProt	LLR -9.12	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.6, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 94 kb · p 0.0042 · regional, not allelic
Overall
CADD	27.3	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 0.00034% European (non-Finnish) · 4/1,175,482 alleles

Filtering AF 8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000249% 4/1,603,644 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.Leu469Ser
Coding: c.1406T>C
MANE Select: NM_019044
Type: single nucleotide variant
Location: chr2:117944031 (GRCh38)
Gene constraint: LOEUF 0.986 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.49 · 4 PDB
Residue 469: the 'sufficient for interaction with washc2c' region

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

Similar variants

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
CCDC93 p.Arg126Gly 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-leu469ser (accessed [today's date]).

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