Is C2CD2 p.Arg428Cys (c.1282C>T) pathogenic?

C2CD2 p.Arg428Cys (c.1282C>T) is classified Uncertain significance in C2CD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-13). AlphaMissense: likely benign (0.1884); Ultra-rare (popmax 0.0165%, mid).

How common is C2CD2 p.Arg428Cys (c.1282C>T) in the general population?

C2CD2 p.Arg428Cys (c.1282C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about C2CD2 p.Arg428Cys (c.1282C>T)?

AlphaMissense predicts likely benign (score 0.1884) — an in-silico prediction, not a clinical call.

C2CD2 p.Arg428Cys

c.1282C>T · rs146922306 · VCV2588084

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1884 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1884	likely benign
REVEL	0.206	benign-leaning
SaProt	LLR -7.17	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 6.9	GERP 2.1, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 65 kb · p 0.00014 · regional, not allelic
Overall
CADD	27.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,058 alleles

Filtering AF 0.0135% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0128%

Overall 0.0133% 215/1,613,962 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0304%	3,288
Middle Easterngrpmax	0.0165%	6,058
European (non-Finnish)	0.0153%	6,519
South Asian	0.011%	9,109
East Asian	0.00668%	14,967
African / African-American	0.00134%	74,906

Remaining individuals 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: C2CD2
Protein: p.Arg428Cys
Coding: c.1282C>T
MANE Select: NM_015500
dbSNP: rs146922306
Type: single nucleotide variant
Location: chr21:41907028 (GRCh38)
Gene constraint: LOEUF 0.924 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.52

Full C2CD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

C2CD2 p.Pro104= Benign ★★ same type
C2CD2 p.Ala123Val Uncertain significance ★ ⚠ same type
C2CD2 p.Ala136Gly Uncertain significance ★ ⚠ same type
C2CD2 p.Ala146Val Uncertain significance ★ ⚠ same type
C2CD2 p.Ala189Thr Uncertain significance ★ ⚠ same type
C2CD2 p.Ala207Val Uncertain significance ★ ⚠ same type
C2CD2 p.Ala345Val Uncertain significance ★ ⚠ same type
C2CD2 p.Ala466Thr 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/c2cd2-p-arg428cys (accessed [today's date]).

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