Is C2CD3 p.Ser466Gly (c.1396A>G) pathogenic?

C2CD3 p.Ser466Gly (c.1396A>G) is classified Conflicting classifications of pathogenicity in C2CD3 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-12-24). AlphaMissense: likely benign (0.109); Ultra-rare (popmax 0.0914%, eas); Associated with Inborn genetic diseases.

What condition is associated with C2CD3 p.Ser466Gly (c.1396A>G)?

C2CD3 p.Ser466Gly (c.1396A>G) is associated with Inborn genetic diseases (ClinVar).

How common is C2CD3 p.Ser466Gly (c.1396A>G) in the general population?

C2CD3 p.Ser466Gly (c.1396A>G) is ultra-rare (popmax 0.0914%, eas) (gnomAD).

What do computational predictors say about C2CD3 p.Ser466Gly (c.1396A>G)?

AlphaMissense predicts likely benign (score 0.109) — an in-silico prediction, not a clinical call.

C2CD3 p.Ser466Gly

c.1396A>G · rs201605347 · VCV1406862

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.109 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0914%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.109	likely benign
REVEL	0.112	moderately benign-leaning
SaProt	LLR -7.32	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.8	GERP 0.73, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 157 kb · p 9.8e-06 · regional, not allelic
Overall
CADD	22.1	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 0.0914% East Asian · 41/44,860 alleles

Filtering AF 0.0692% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0614%

Overall 0.00341% 55/1,612,198 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0914%	1,094
Remaining individualsnot grpmax-eligible	0.0176%	5,677
African / African-American	0.00133%	74,984
European (non-Finnish)	0.00017%	589,157

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: C2CD3
Protein: p.Ser466Gly
Coding: c.1396A>G
MANE Select: NM_001286577
dbSNP: rs201605347
Type: single nucleotide variant
Location: chr11:74118352 (GRCh38)
Gene constraint: LOEUF 0.637 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 55.65
Residue 466: a modified residue (phosphoserine)

Full C2CD3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

C2CD3 c.2085+5G>A Uncertain significance ★★ same condition
C2CD3 c.4951+6C>T Uncertain significance ★★ same condition
C2CD3 p.Ala1382Pro Uncertain significance ★★ ⚠ same condition
C2CD3 p.Ala1777Thr Uncertain significance ★★ ⚠ same condition
C2CD3 p.Ala95Thr Uncertain significance ★★ ⚠ same condition
C2CD3 p.Arg1122Ile Uncertain significance ★★ ⚠ same condition
C2CD3 p.Arg1145His Uncertain significance ★★ ⚠ same condition
C2CD3 p.Arg1183His Uncertain significance ★★ ⚠ same condition

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/c2cd3-p-ser466gly (accessed [today's date]).

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