Is C2CD3 p.Tyr1339Cys (c.4016A>G) pathogenic?

C2CD3 p.Tyr1339Cys (c.4016A>G) is classified Uncertain significance in C2CD3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-04). AlphaMissense: ambiguous (0.3899); Very rare (popmax 0.00348%, amr); Associated with Inborn genetic diseases.

What condition is associated with C2CD3 p.Tyr1339Cys (c.4016A>G)?

C2CD3 p.Tyr1339Cys (c.4016A>G) is associated with Inborn genetic diseases (ClinVar).

How common is C2CD3 p.Tyr1339Cys (c.4016A>G) in the general population?

C2CD3 p.Tyr1339Cys (c.4016A>G) is very rare (popmax 0.00348%, amr) (gnomAD).

What do computational predictors say about C2CD3 p.Tyr1339Cys (c.4016A>G)?

AlphaMissense predicts ambiguous (score 0.3899) — an in-silico prediction, not a clinical call.

C2CD3 p.Tyr1339Cys

c.4016A>G · rs1184333480 · VCV2016658

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3899 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00348%, amr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3899	ambiguous
REVEL	0.439	indeterminate
SaProt	LLR -10.98	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP 0.43, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 157 kb · p 9.8e-06 · regional, not allelic
Overall
CADD	24.5	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 0.00348% Admixed American · 2/57,486 alleles

Filtering AF 0.00103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000833%

Overall 0.00143% 23/1,602,924 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00348%	28,743
Remaining individualsnot grpmax-eligible	0.00323%	30,964
European (non-Finnish)	0.00162%	61,861

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.Tyr1339Cys
Coding: c.4016A>G
MANE Select: NM_001286577
dbSNP: rs1184333480
Type: single nucleotide variant
Location: chr11:74078702 (GRCh38)
Gene constraint: LOEUF 0.637 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 55.65
Residue 1339: the c2 4 domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

C2CD3 c.2085+5G>A Uncertain significance ★★ same condition
C2CD3 c.4951+6C>T Uncertain significance ★★ same condition
C2CD3 p.Ala1382Pro Uncertain significance ★★ ⚠ same condition
C2CD3 p.Ala1777Thr Uncertain significance ★★ ⚠ same condition
C2CD3 p.Ala95Thr Uncertain significance ★★ ⚠ same condition
C2CD3 p.Arg1122Ile Uncertain significance ★★ ⚠ same condition
C2CD3 p.Arg1145His Uncertain significance ★★ ⚠ same condition
C2CD3 p.Arg1183His Uncertain significance ★★ ⚠ same condition

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-tyr1339cys (accessed [today's date]).

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