Is CC2D2B p.Arg1345Pro (c.4034G>C) pathogenic?

CC2D2B p.Arg1345Pro (c.4034G>C) is classified Uncertain significance in CC2D2B (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-20). AlphaMissense: likely pathogenic (0.876); Ultra-rare (popmax 0.0357%, sas).

How common is CC2D2B p.Arg1345Pro (c.4034G>C) in the general population?

CC2D2B p.Arg1345Pro (c.4034G>C) is ultra-rare (popmax 0.0357%, sas) (gnomAD).

What do computational predictors say about CC2D2B p.Arg1345Pro (c.4034G>C)?

AlphaMissense predicts likely pathogenic (score 0.876) — an in-silico prediction, not a clinical call.

CC2D2B p.Arg1345Pro

c.4034G>C · VCV3263727

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.876 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0357%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.876	likely pathogenic · top 5% in CC2D2B
REVEL	0.357	indeterminate
SaProt	LLR -14.69	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP 0.72, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 41 kb · p 0.0003 · regional, not allelic
Overall
CADD	23.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0357% South Asian · 30/83,948 alleles

Filtering AF 0.0257% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0223%

Overall 0.00206% 32/1,551,128 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0357%	2,798
Middle Eastern	0.0166%	6,014
European (non-Finnish)	8.72e-05%	1,146,803

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: CC2D2B
Protein: p.Arg1345Pro
Coding: c.4034G>C
MANE Select: NM_001349008
Type: single nucleotide variant
Location: chr10:96027298 (GRCh38)
Gene constraint: LOEUF 0.832 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.49

Full CC2D2B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CC2D2B p.Arg1101Gln Uncertain significance ★ ⚠ same type
CC2D2B p.Arg1329Gln Uncertain significance ★ ⚠ same type
CC2D2B p.Asn1422Ser Uncertain significance ★ ⚠ same type
CC2D2B p.Asp1248Asn Uncertain significance ★ ⚠ same type
CC2D2B p.Asp1312Glu Uncertain significance ★ ⚠ same type
CC2D2B p.Cys1234Arg Uncertain significance ★ ⚠ same type
CC2D2B p.Cys985Tyr Uncertain significance ★ ⚠ same type
CC2D2B p.Gln1128Glu 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/cc2d2b-p-arg1345pro (accessed [today's date]).

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