Is C2CD3 p.Asn2278Ser (c.6833A>G) pathogenic?

C2CD3 p.Asn2278Ser (c.6833A>G) is classified Likely benign in C2CD3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-06-01). AlphaMissense: likely benign (0.1467); Rare (popmax 0.335%, mid).

How common is C2CD3 p.Asn2278Ser (c.6833A>G) in the general population?

C2CD3 p.Asn2278Ser (c.6833A>G) is rare (popmax 0.335%, mid) (gnomAD).

What do computational predictors say about C2CD3 p.Asn2278Ser (c.6833A>G)?

AlphaMissense predicts likely benign (score 0.1467) — an in-silico prediction, not a clinical call.

C2CD3 p.Asn2278Ser

c.6833A>G · rs199993353 · VCV444263

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1467 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.335%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1467	likely benign
REVEL	0.056	moderately benign-leaning
SaProt	LLR -4.78	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.48	acceptor loss, 20 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 7.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 157 kb · p 9.8e-06 · regional, not allelic
Overall
CADD	22.5	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 0.335% Middle Eastern · 20/5,962 alleles

Filtering AF 0.222% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.186%

Overall 0.0284% 436/1,535,976 alleles · rare

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	0.548%	182
Middle Easterngrpmax	0.335%	298
Admixed American	0.0726%	1,378
Remaining individualsnot grpmax-eligible	0.0517%	1,936
European (non-Finnish)	0.0281%	3,562
South Asian	0.0143%	7,005
African / African-American	0.00957%	10,448
Ashkenazi Jewishnot grpmax-eligible	0.00698%	14,320

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Asn2278Ser
Coding: c.6833A>G
MANE Select: NM_001286577
dbSNP: rs199993353
Type: single nucleotide variant
Location: chr11:74028375 (GRCh38)
Gene constraint: LOEUF 0.637 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 55.65

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-asn2278ser (accessed [today's date]).

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