Is C2CD3 p.Ser528Arg (c.1584T>A) pathogenic?

C2CD3 p.Ser528Arg (c.1584T>A) is classified Likely benign in C2CD3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-07). AlphaMissense: likely pathogenic (0.6562); Rare (popmax 0.288%, eas).

How common is C2CD3 p.Ser528Arg (c.1584T>A) in the general population?

C2CD3 p.Ser528Arg (c.1584T>A) is rare (popmax 0.288%, eas) (gnomAD).

What do computational predictors say about C2CD3 p.Ser528Arg (c.1584T>A)?

AlphaMissense predicts likely pathogenic (score 0.6562) — an in-silico prediction, not a clinical call.

C2CD3 p.Ser528Arg

c.1584T>A · rs137913425 · VCV1621970

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6562 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.288%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6562	likely pathogenic
REVEL	0.167	moderately benign-leaning
SaProt	LLR -10.67	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7	GERP -0.48, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 157 kb · p 9.8e-06 · regional, not allelic
Overall
CADD	21.9	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 0.288% East Asian · 129/44,846 alleles

Filtering AF 0.247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.232%

Overall 0.00867% 140/1,613,918 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.288%	348
Remaining individualsnot grpmax-eligible	0.0144%	6,945
South Asian	0.0022%	45,540

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.Ser528Arg
Coding: c.1584T>A
MANE Select: NM_001286577
dbSNP: rs137913425
Type: single nucleotide variant
Location: chr11:74114530 (GRCh38)
Gene constraint: LOEUF 0.637 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 55.65
Residue 528: the c2 1 domain

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-ser528arg (accessed [today's date]).

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