Is C2CD3 p.Ser1075Arg (c.3223A>C) pathogenic?

C2CD3 p.Ser1075Arg (c.3223A>C) is classified Uncertain significance in C2CD3 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-01-24). AlphaMissense: likely pathogenic (0.6558); Ultra-rare (popmax 0.0107%, nfe); Associated with Inborn genetic diseases.

What condition is associated with C2CD3 p.Ser1075Arg (c.3223A>C)?

C2CD3 p.Ser1075Arg (c.3223A>C) is associated with Inborn genetic diseases (ClinVar).

How common is C2CD3 p.Ser1075Arg (c.3223A>C) in the general population?

C2CD3 p.Ser1075Arg (c.3223A>C) is ultra-rare (popmax 0.0107%, nfe) (gnomAD).

What do computational predictors say about C2CD3 p.Ser1075Arg (c.3223A>C)?

AlphaMissense predicts likely pathogenic (score 0.6558) — an in-silico prediction, not a clinical call.

C2CD3 p.Ser1075Arg

c.3223A>C · rs764477521 · VCV598652

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.6558 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0107%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6558	likely pathogenic
REVEL	0.145	moderately benign-leaning
SaProt	LLR -9.60	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 5.2	GERP 1.8, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 157 kb · p 9.8e-06 · regional, not allelic
Overall
CADD	25.9	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 0.0107% European (non-Finnish) · 126/1,179,946 alleles

Filtering AF 0.00911% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00855%

Overall 0.00812% 131/1,613,998 alleles · ultra-rare exomes 123/1,461,748 · genomes 8/152,250 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0107%	9,365
Remaining individualsnot grpmax-eligible	0.0048%	20,828
Admixed American	0.00333%	30,002

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.Ser1075Arg
Coding: c.3223A>C
MANE Select: NM_001286577
dbSNP: rs764477521
Type: single nucleotide variant
Location: chr11:74093937 (GRCh38)
Gene constraint: LOEUF 0.637 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 55.65
Residue 1075: the c2 3 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-ser1075arg (accessed [today's date]).

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