Is C2CD3 p.Cys1281fs (c.3842dup) pathogenic?

C2CD3 p.Cys1281fs (c.3842dup) is classified Pathogenic in C2CD3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-17). Very rare (popmax 0.00254%, nfe).

How common is C2CD3 p.Cys1281fs (c.3842dup) in the general population?

C2CD3 p.Cys1281fs (c.3842dup) is very rare (popmax 0.00254%, nfe) (gnomAD).

C2CD3 p.Cys1281fs

c.3842dup · VCV3711114

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00254%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 21 of 33
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 6.2	GERP -0.58, phastCons 1
Overall
CADD	33.0	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 0.00254% European (non-Finnish) · 30/1,180,042 alleles

Filtering AF 0.0018% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00156%

Overall 0.00186% 30/1,614,064 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: C2CD3
Protein: p.Cys1281fs
Coding: c.3842dup
MANE Select: NM_001286577
Type: Duplication
Location: chr11:74085685 (GRCh38)
Gene constraint: LOEUF 0.637 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 55.65
Residue 1281: the c2 4 domain

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

Similar variants

C2CD3 p.Cys1281Ser Uncertain significance ★ ⚠ same residue
C2CD3 p.Cys1281= Likely benign ★ same residue
C2CD3 p.His904fs Pathogenic/Likely pathogenic ★★ same type
C2CD3 p.Val332fs Pathogenic/Likely pathogenic ★★ same type
C2CD3 p.Ala1017fs Pathogenic ★ same type
C2CD3 p.Arg18fs Pathogenic ★ same type
C2CD3 p.Asn1154fs Pathogenic ★ same type
C2CD3 p.Asn1427fs Pathogenic ★ 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-cys1281fs (accessed [today's date]).

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