Is C2CD6 p.Arg1779Ter (c.5335C>T) pathogenic?

C2CD6 p.Arg1779Ter (c.5335C>T) is classified Uncertain significance in C2CD6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-04). Rare (popmax 0.363%, mid); Associated with spermatogenic failure 68.

What condition is associated with C2CD6 p.Arg1779Ter (c.5335C>T)?

C2CD6 p.Arg1779Ter (c.5335C>T) is associated with spermatogenic failure 68 (ClinVar).

How common is C2CD6 p.Arg1779Ter (c.5335C>T) in the general population?

C2CD6 p.Arg1779Ter (c.5335C>T) is rare (popmax 0.363%, mid) (gnomAD).

C2CD6 p.Arg1779Ter

c.5335C>T · rs140775049 · VCV3067882

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

rare (popmax 0.363%, mid)

Conditions

spermatogenic failure 68

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	escapes	premature termination codon in the last exon (16 of 16) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP -2.2, phastCons 0.001
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 0.363% Middle Eastern · 22/6,062 alleles

Filtering AF 0.246% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.207%

Overall 0.0533% 860/1,614,012 alleles · rare

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	2.3%	43
Middle Easterngrpmax	0.363%	276
Ashkenazi Jewishnot grpmax-eligible	0.264%	379
Admixed American	0.203%	492
Remaining individualsnot grpmax-eligible	0.102%	977
European (non-Finnish)	0.0432%	2,314
South Asian	0.0318%	3,140
African / African-American	0.016%	6,249
East Asian	0.00223%	44,874
Finnishnot grpmax-eligible	0.00156%	64,002

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: C2CD6
Protein: p.Arg1779Ter
Coding: c.5335C>T
MANE Select: NM_001168221
dbSNP: rs140775049
Type: single nucleotide variant
Location: chr2:201487740 (GRCh38)
Gene constraint: LOEUF 0.908 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 39.82

Full C2CD6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

spermatogenic failure 68 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

C2CD6 p.His113Arg Pathogenic ⚠ same condition
C2CD6 p.Ala1682Thr Uncertain significance ★ same type
C2CD6 p.Ala427Gly Uncertain significance ★ ⚠ same type
C2CD6 p.Ala54Pro Uncertain significance ★ ⚠ same type
C2CD6 p.Ala54Ser Uncertain significance ★ ⚠ same type
C2CD6 p.Ala646Ser Uncertain significance ★ same type
C2CD6 p.Ala827Asp Uncertain significance ★ same type
C2CD6 p.Arg1134Cys 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/c2cd6-p-arg1779ter (accessed [today's date]).

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