Is CCT2 p.Arg322Cys (c.964C>T) pathogenic?

CCT2 p.Arg322Cys (c.964C>T) is classified Uncertain significance in CCT2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-04). AlphaMissense: likely pathogenic (0.7887); Ultra-rare (popmax 0.0701%, amr).

How common is CCT2 p.Arg322Cys (c.964C>T) in the general population?

CCT2 p.Arg322Cys (c.964C>T) is ultra-rare (popmax 0.0701%, amr) (gnomAD).

What do computational predictors say about CCT2 p.Arg322Cys (c.964C>T)?

AlphaMissense predicts likely pathogenic (score 0.7887) — an in-silico prediction, not a clinical call.

CCT2 p.Arg322Cys

c.964C>T · rs781508198 · VCV1009273

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7887 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0701%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7887	likely pathogenic
REVEL	0.777	moderately pathogenic-leaning
SaProt	LLR -14.80	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 1.3, phastCons 1
Regional constraint	o/e 0.41	unconstrained · MANE · 4,084 bp · p 8e-06 · regional, not allelic
Overall
CADD	32.0	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 0.0701% Admixed American · 42/59,888 alleles

Filtering AF 0.0533% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0474%

Overall 0.00504% 81/1,607,868 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0701%	1,426
Remaining individualsnot grpmax-eligible	0.00643%	15,554
East Asian	0.00446%	22,399
European (non-Finnish)	0.00264%	37,899
African / African-American	0.00134%	74,786
South Asian	0.0011%	90,828

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: CCT2
Protein: p.Arg322Cys
Coding: c.964C>T
MANE Select: NM_006431
dbSNP: rs781508198
Type: single nucleotide variant
Location: chr12:69593595 (GRCh38)
Gene constraint: LOEUF 0.445 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 89.85 · 71 PDB
Residue 322: an α-helix

Full CCT2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCT2 p.Arg322His Uncertain significance ★ ⚠ same residue
CCT2 p.Arg322= Likely benign ★ same residue
CCT2 p.Ala128Thr Uncertain significance ★★ ⚠ same type
CCT2 p.Ala133Val Uncertain significance ★★ ⚠ same type
CCT2 p.Ala145Val Uncertain significance ★★ ⚠ same type
CCT2 p.Arg156Cys Uncertain significance ★★ ⚠ same type
CCT2 p.Arg255Gln Uncertain significance ★★ ⚠ same type
CCT2 p.Arg255Trp 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/cct2-p-arg322cys (accessed [today's date]).

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