Is CCT2 p.Arg281Cys (c.841C>T) pathogenic?

CCT2 p.Arg281Cys (c.841C>T) is classified Uncertain significance in CCT2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-09). AlphaMissense: likely benign (0.1616); Ultra-rare (popmax 0.0176%, sas).

How common is CCT2 p.Arg281Cys (c.841C>T) in the general population?

CCT2 p.Arg281Cys (c.841C>T) is ultra-rare (popmax 0.0176%, sas) (gnomAD).

What do computational predictors say about CCT2 p.Arg281Cys (c.841C>T)?

AlphaMissense predicts likely benign (score 0.1616) — an in-silico prediction, not a clinical call.

CCT2 p.Arg281Cys

c.841C>T · rs551629629 · VCV1016667

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1616 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0176%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1616	likely benign
REVEL	0.648	pathogenic-leaning
SaProt	LLR -12.22	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.98 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.8	GERP 1.3, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 7,571 bp · p 0.023 · regional, not allelic
Overall
CADD	30.0	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 0.0176% South Asian · 16/91,068 alleles

Filtering AF 0.011% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00888%

Overall 0.00205% 33/1,613,140 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0176%	5,692
Middle Eastern	0.0165%	6,048
Admixed American	0.00667%	14,995
African / African-American	0.00533%	18,746
Remaining individualsnot grpmax-eligible	0.0032%	31,237
European (non-Finnish)	0.000509%	196,536

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.Arg281Cys
Coding: c.841C>T
MANE Select: NM_006431
dbSNP: rs551629629
Type: single nucleotide variant
Location: chr12:69593066 (GRCh38)
Gene constraint: LOEUF 0.445 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 89.85 · 71 PDB
Residue 281: an α-helix

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

Similar variants

CCT2 p.Arg281His Uncertain significance ★★ ⚠ 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
CCT2 p.Arg322Cys 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-arg281cys (accessed [today's date]).

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