Is C2CD6 p.Asp295Tyr (c.883G>T) pathogenic?

C2CD6 p.Asp295Tyr (c.883G>T) is classified Uncertain significance in C2CD6 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-26). AlphaMissense: ambiguous (0.4983); Ultra-rare (popmax 0.0165%, mid).

How common is C2CD6 p.Asp295Tyr (c.883G>T) in the general population?

C2CD6 p.Asp295Tyr (c.883G>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about C2CD6 p.Asp295Tyr (c.883G>T)?

AlphaMissense predicts ambiguous (score 0.4983) — an in-silico prediction, not a clinical call.

C2CD6 p.Asp295Tyr

c.883G>T · rs376366248 · VCV2514117

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4983 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4983	ambiguous
REVEL	0.196	benign-leaning
SaProt	LLR -7.18	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.4	GERP 0.97, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 83 kb · p 0.41 · regional, not allelic
Overall
CADD	24.9	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 0.0165% Middle Eastern · 1/6,070 alleles

Filtering AF 0.00122% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00174% 28/1,610,402 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,070
Remaining individualsnot grpmax-eligible	0.00802%	12,471
European (non-Finnish)	0.00187%	53,573

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.Asp295Tyr
Coding: c.883G>T
MANE Select: NM_001168221
dbSNP: rs376366248
Type: single nucleotide variant
Location: chr2:201565823 (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-asp295tyr (accessed [today's date]).

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