Is C2CD6 p.His113Arg (c.338A>G) pathogenic?

C2CD6 p.His113Arg (c.338A>G) is classified Pathogenic in C2CD6 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2022-03-21). AlphaMissense: likely benign (0.296); Absent from gnomAD v4.1; Associated with spermatogenic failure 68.

What condition is associated with C2CD6 p.His113Arg (c.338A>G)?

C2CD6 p.His113Arg (c.338A>G) is associated with spermatogenic failure 68 (ClinVar).

How common is C2CD6 p.His113Arg (c.338A>G) in the general population?

C2CD6 p.His113Arg (c.338A>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about C2CD6 p.His113Arg (c.338A>G)?

AlphaMissense predicts likely benign (score 0.296) — an in-silico prediction, not a clinical call.

C2CD6 p.His113Arg

c.338A>G · rs2105806061 · VCV1345025

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.296 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

spermatogenic failure 68

Computational evidence

Protein change
AlphaMissense	0.296	likely benign ⚠ discordant with ClinVar
REVEL	0.408	indeterminate
SaProt	LLR -6.74	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 2.7	GERP -0.73, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 83 kb · p 0.41 · regional, not allelic
Overall
CADD	22.1	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: C2CD6
Protein: p.His113Arg
Coding: c.338A>G
MANE Select: NM_001168221
dbSNP: rs2105806061
Type: single nucleotide variant
Location: chr2:201603256 (GRCh38)
Gene constraint: LOEUF 0.908 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 39.82
Residue 113: the c2 domain; a UniProt-annotated variant site (in spgf68; uncertain significance)

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.Arg1779Ter Uncertain significance ★ 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-his113arg (accessed [today's date]).

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