Is C2CD3 p.Arg666Ter (c.1996C>T) pathogenic?

C2CD3 p.Arg666Ter (c.1996C>T) is classified Pathogenic in C2CD3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-04-10). Very rare (popmax 0.00333%, amr); Associated with orofaciodigital syndrome type 14.

What condition is associated with C2CD3 p.Arg666Ter (c.1996C>T)?

C2CD3 p.Arg666Ter (c.1996C>T) is associated with orofaciodigital syndrome type 14 (ClinVar).

How common is C2CD3 p.Arg666Ter (c.1996C>T) in the general population?

C2CD3 p.Arg666Ter (c.1996C>T) is very rare (popmax 0.00333%, amr) (gnomAD).

C2CD3 p.Arg666Ter

c.1996C>T · rs1382351297 · VCV3014634

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Conditions

orofaciodigital syndrome type 14

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 13 of 33
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP -1.4, phastCons 1
Overall
CADD	35.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00333% Admixed American · 2/60,000 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000342% 5/1,461,322 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,000
East Asian	0.00223%	44,870
South Asian	0.0011%	91,068
European (non-Finnish)	8.48e-05%	1,179,572

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.Arg666Ter
Coding: c.1996C>T
MANE Select: NM_001286577
dbSNP: rs1382351297
Type: single nucleotide variant
Location: chr11:74106460 (GRCh38)
Gene constraint: LOEUF 0.637 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 55.65
Residue 666: the c2 1 domain

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

Disease context

orofaciodigital syndrome type 14 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

C2CD3 p.Arg666Gln Uncertain significance ★ ⚠ same residue
C2CD3 c.3911-2A>T Pathogenic/Likely pathogenic ★★ same condition
C2CD3 p.Arg621Ter Pathogenic/Likely pathogenic ★★ same condition
C2CD3 c.5495+4A>G Uncertain significance ★★ same condition
C2CD3 c.5882-332A>G Uncertain significance ★★ same condition
C2CD3 p.Arg1061Thr Uncertain significance ★★ ⚠ same condition
C2CD3 p.Arg1248Cys Uncertain significance ★★ ⚠ same condition
C2CD3 p.Arg1553Gln 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-arg666ter (accessed [today's date]).

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