Is CCT2 p.Ile493Val (c.1477A>G) pathogenic?

CCT2 p.Ile493Val (c.1477A>G) is classified Uncertain significance in CCT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-04). AlphaMissense: likely benign (0.1072); Ultra-rare (popmax 0.0178%, eas).

How common is CCT2 p.Ile493Val (c.1477A>G) in the general population?

CCT2 p.Ile493Val (c.1477A>G) is ultra-rare (popmax 0.0178%, eas) (gnomAD).

What do computational predictors say about CCT2 p.Ile493Val (c.1477A>G)?

AlphaMissense predicts likely benign (score 0.1072) — an in-silico prediction, not a clinical call.

CCT2 p.Ile493Val

c.1477A>G · rs559620948 · VCV1054156

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1072 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0178%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1072	likely benign
REVEL	0.112	moderately benign-leaning
SaProt	LLR -4.03	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7	GERP 1, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 4,143 bp · p 0.12 · regional, not allelic
Overall
CADD	19.39	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 0.0178% East Asian · 8/44,872 alleles

Filtering AF 0.00884% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00641%

Overall 0.000682% 11/1,613,906 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0178%	5,609
Admixed American	0.00333%	30,013
Remaining individualsnot grpmax-eligible	0.0016%	62,490

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.Ile493Val
Coding: c.1477A>G
MANE Select: NM_006431
dbSNP: rs559620948
Type: single nucleotide variant
Location: chr12:69599904 (GRCh38)
Gene constraint: LOEUF 0.445 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 89.85 · 71 PDB

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

Similar variants

CCT2 p.Ile493Arg 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.Arg281Cys 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-ile493val (accessed [today's date]).

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