Is C2CD3 p.Arg1496Ter (c.4486C>T) pathogenic?

C2CD3 p.Arg1496Ter (c.4486C>T) is classified Likely pathogenic in C2CD3 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-07). Very rare (popmax 0.00267%, afr).

How common is C2CD3 p.Arg1496Ter (c.4486C>T) in the general population?

C2CD3 p.Arg1496Ter (c.4486C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

C2CD3 p.Arg1496Ter

c.4486C>T · rs1189478751 · VCV1690523

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

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 23 of 33
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.5	GERP -0.44, phastCons 1
Overall
CADD	37.0	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 0.00267% African / African-American · 2/74,890 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000496% 8/1,613,938 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,445
Remaining individualsnot grpmax-eligible	0.0016%	62,486
European (non-Finnish)	0.000424%	236,001

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.Arg1496Ter
Coding: c.4486C>T
MANE Select: NM_001286577
dbSNP: rs1189478751
Type: single nucleotide variant
Location: chr11:74078232 (GRCh38)
Gene constraint: LOEUF 0.637 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 55.65
Residue 1496: the c2 5 domain

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

Similar variants

C2CD3 p.Arg1496Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
C2CD3 c.3911-2A>T Pathogenic/Likely pathogenic ★★ same type
C2CD3 p.Arg621Ter Pathogenic/Likely pathogenic ★★ same type
C2CD3 p.Arg666Ter Pathogenic ★★ same type
C2CD3 p.Arg768Ter Pathogenic/Likely pathogenic ★★ same type
C2CD3 p.Tyr173Ter Pathogenic/Likely pathogenic ★★ same type
C2CD3 c.2085+5G>A Uncertain significance ★★ same type
C2CD3 c.4951+6C>T 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/c2cd3-p-arg1496ter (accessed [today's date]).

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