Is C2CD3 p.Arg1219Gln (c.3656G>A) pathogenic?

C2CD3 p.Arg1219Gln (c.3656G>A) is classified Benign in C2CD3 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0539); Common (popmax 52.9%, afr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about C2CD3 p.Arg1219Gln (c.3656G>A)?

AlphaMissense predicts likely benign (score 0.0539) — an in-silico prediction, not a clinical call.

C2CD3 p.Arg1219Gln

Q: How common is C2CD3 p.Arg1219Gln (c.3656G>A) in the general population?

C2CD3 p.Arg1219Gln (c.3656G>A) is common (popmax 52.9%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.3656G>A · rs826058 · VCV1599854

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0539 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 52.9%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0539	likely benign
REVEL	0.066	moderately benign-leaning
SaProt	LLR -7.24	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.9	GERP 0.52, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 157 kb · p 9.8e-06 · regional, not allelic
Overall
CADD	17.83	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 52.9% African / African-American · 39,554/74,824 alleles

Filtering AF 52.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 52.2%

Overall 30.6% 493,634/1,611,248 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	52.9%	2
Admixed American	38.1%	3
Middle Eastern	36.8%	3
Amishnot grpmax-eligible	31.9%	3
Remaining individualsnot grpmax-eligible	30.5%	3
European (non-Finnish)	29.8%	3
Ashkenazi Jewishnot grpmax-eligible	29.2%	3
Finnishnot grpmax-eligible	28%	4
South Asian	26.3%	4
East Asian	19.4%	5

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.Arg1219Gln
Coding: c.3656G>A
MANE Select: NM_001286577
dbSNP: rs826058
Type: single nucleotide variant
Location: chr11:74085872 (GRCh38)
Gene constraint: LOEUF 0.637 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 55.65
Residue 1219: the c2 4 domain; a UniProt-annotated variant site (in)

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

Similar variants

C2CD3 c.3911-2A>T Pathogenic/Likely pathogenic ★★ same type
C2CD3 p.Arg621Ter Pathogenic/Likely pathogenic ★★ same type
C2CD3 p.Arg666Ter Pathogenic ★★ same type
C2CD3 p.Arg768Ter Pathogenic/Likely pathogenic ★★ same type
C2CD3 p.Tyr173Ter Pathogenic/Likely pathogenic ★★ same type
C2CD3 c.2085+5G>A Uncertain significance ★★ same type
C2CD3 c.4951+6C>T Uncertain significance ★★ same type
C2CD3 c.5495+4A>G 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/c2cd3-p-arg1219gln (accessed [today's date]).

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