Is CC2D2A p.Ser1069Pro (c.3205T>C) pathogenic?

CC2D2A p.Ser1069Pro (c.3205T>C) is classified Uncertain significance in CC2D2A (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-09). AlphaMissense: likely benign (0.0714); Very rare (popmax 0.00568%, nfe).

How common is CC2D2A p.Ser1069Pro (c.3205T>C) in the general population?

CC2D2A p.Ser1069Pro (c.3205T>C) is very rare (popmax 0.00568%, nfe) (gnomAD).

What do computational predictors say about CC2D2A p.Ser1069Pro (c.3205T>C)?

AlphaMissense predicts likely benign (score 0.0714) — an in-silico prediction, not a clinical call.

CC2D2A p.Ser1069Pro

c.3205T>C · VCV4966582

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0714 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00568%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0714	likely benign
REVEL	0.423	indeterminate
SaProt	LLR -6.40	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.9	GERP 1.2, phastCons 0.52
Regional constraint	o/e 0.96	unconstrained · MANE · 104 kb · p 0.09 · regional, not allelic
Overall
CADD	20.4	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 0.00568% European (non-Finnish) · 67/1,179,550 alleles

Filtering AF 0.00454% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00417%

Overall 0.00428% 69/1,613,110 alleles · very rare exomes 68/1,461,004 · genomes 1/152,106 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00568%	17,605
Remaining individualsnot grpmax-eligible	0.0032%	31,217

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: CC2D2A
Protein: p.Ser1069Pro
Coding: c.3205T>C
MANE Select: NM_001378615
Type: single nucleotide variant
Location: chr4:15567399 (GRCh38)
Gene constraint: LOEUF 0.854 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 69.46
Residue 1069: the c2 domain; the 'disordered' region

Full CC2D2A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CC2D2A p.Ser1069= Likely benign ★ same residue
CC2D2A c.1017+1G>A Pathogenic/Likely pathogenic ★★ same type
CC2D2A c.1149+1G>A Pathogenic/Likely pathogenic ★★ same type
CC2D2A c.123+2T>G Likely pathogenic ★★ same type
CC2D2A c.1359+1G>A Pathogenic/Likely pathogenic ★★ same type
CC2D2A c.1359+1G>C Likely pathogenic ★★ same type
CC2D2A c.1466+1G>A Likely pathogenic ★★ same type
CC2D2A c.1466+2T>C Likely pathogenic ★★ 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/cc2d2a-p-ser1069pro (accessed [today's date]).

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