Is CCT2 p.Met488Thr (c.1463T>C) pathogenic?

CCT2 p.Met488Thr (c.1463T>C) is classified Uncertain significance in CCT2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-25). AlphaMissense: likely pathogenic (0.671); Ultra-rare (popmax 0.01%, amr).

How common is CCT2 p.Met488Thr (c.1463T>C) in the general population?

CCT2 p.Met488Thr (c.1463T>C) is ultra-rare (popmax 0.01%, amr) (gnomAD).

What do computational predictors say about CCT2 p.Met488Thr (c.1463T>C)?

AlphaMissense predicts likely pathogenic (score 0.671) — an in-silico prediction, not a clinical call.

CCT2 p.Met488Thr

c.1463T>C · rs774243986 · VCV839650

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.671 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.01%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.671	likely pathogenic
REVEL	0.888	moderately pathogenic-leaning
SaProt	LLR -7.01	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.1, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 4,143 bp · p 0.12 · regional, not allelic
Overall
CADD	23.9	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 0.01% Admixed American · 6/59,974 alleles

Filtering AF 0.00428% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.00347% 56/1,613,512 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.01%	9,996
African / African-American	0.00801%	12,487
Remaining individualsnot grpmax-eligible	0.00641%	15,611
South Asian	0.0033%	30,331
European (non-Finnish)	0.00305%	32,769
East Asian	0.00223%	44,882

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.Met488Thr
Coding: c.1463T>C
MANE Select: NM_006431
dbSNP: rs774243986
Type: single nucleotide variant
Location: chr12:69599890 (GRCh38)
Gene constraint: LOEUF 0.445 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 89.85 · 71 PDB
Residue 488: an α-helix

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

Similar variants

CCT2 p.Met488Ile Uncertain significance ★★ ⚠ same residue
CCT2 p.Met488Val 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

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-met488thr (accessed [today's date]).

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