Is C2CD3 p.Ser865Cys (c.2594C>G) pathogenic?

C2CD3 p.Ser865Cys (c.2594C>G) is classified Conflicting classifications of pathogenicity in C2CD3 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-12-06). AlphaMissense: likely benign (0.0807); Ultra-rare (popmax 0.0647%, eas); Associated with Inborn genetic diseases.

What condition is associated with C2CD3 p.Ser865Cys (c.2594C>G)?

C2CD3 p.Ser865Cys (c.2594C>G) is associated with Inborn genetic diseases, Joubert syndrome (ClinVar).

How common is C2CD3 p.Ser865Cys (c.2594C>G) in the general population?

C2CD3 p.Ser865Cys (c.2594C>G) is ultra-rare (popmax 0.0647%, eas) (gnomAD).

What do computational predictors say about C2CD3 p.Ser865Cys (c.2594C>G)?

AlphaMissense predicts likely benign (score 0.0807) — an in-silico prediction, not a clinical call.

C2CD3 p.Ser865Cys

c.2594C>G · rs148264086 · VCV389613

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0807 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0647%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0807	likely benign
REVEL	0.578	indeterminate
SaProt	LLR -6.62	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 0.047, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 157 kb · p 9.8e-06 · regional, not allelic
Overall
CADD	23.4	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 0.0647% East Asian · 29/44,840 alleles

Filtering AF 0.0462% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.04%

Overall 0.00564% 91/1,612,324 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0647%	1,546
Remaining individualsnot grpmax-eligible	0.0641%	1,561
African / African-American	0.0133%	7,494
South Asian	0.00331%	30,191
Admixed American	0.00168%	59,540
European (non-Finnish)	0.000678%	147,438

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.Ser865Cys
Coding: c.2594C>G
MANE Select: NM_001286577
dbSNP: rs148264086
Type: single nucleotide variant
Location: chr11:74100663 (GRCh38)
Gene constraint: LOEUF 0.637 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 55.65
Residue 865: the c2 2 domain

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

Also linked: Joubert syndrome

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-ser865cys (accessed [today's date]).

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