Is C2CD6 p.Ser293Tyr (c.878C>A) pathogenic?

C2CD6 p.Ser293Tyr (c.878C>A) is classified Uncertain significance in C2CD6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-28). AlphaMissense: likely pathogenic (0.8086); Very rare (popmax 0.00268%, afr).

How common is C2CD6 p.Ser293Tyr (c.878C>A) in the general population?

C2CD6 p.Ser293Tyr (c.878C>A) is very rare (popmax 0.00268%, afr) (gnomAD).

What do computational predictors say about C2CD6 p.Ser293Tyr (c.878C>A)?

AlphaMissense predicts likely pathogenic (score 0.8086) — an in-silico prediction, not a clinical call.

C2CD6 p.Ser293Tyr

c.878C>A · rs759109388 · VCV3135976

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8086 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00268%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8086	likely pathogenic · top 8% in C2CD6
REVEL	0.287	benign-leaning
SaProt	LLR -7.69	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 83 kb · p 0.41 · regional, not allelic
Overall
CADD	25.7	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

Grpmax group 0.00268% African / African-American · 2/74,698 alleles

Filtering AF 0.000444% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.00198% 3/151,842 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00268%	37,349
Admixed American	0.00167%	59,858

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.Ser293Tyr
Coding: c.878C>A
MANE Select: NM_001168221
dbSNP: rs759109388
Type: single nucleotide variant
Location: chr2:201565828 (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

Similar variants

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
C2CD6 p.Arg1134His 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-ser293tyr (accessed [today's date]).

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