Is CCT2 p.Ser458Asn (c.1373G>A) pathogenic?

CCT2 p.Ser458Asn (c.1373G>A) is classified Uncertain significance in CCT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-02). AlphaMissense: likely pathogenic (0.8613); Very rare (popmax 0.00638%, nfe).

How common is CCT2 p.Ser458Asn (c.1373G>A) in the general population?

CCT2 p.Ser458Asn (c.1373G>A) is very rare (popmax 0.00638%, nfe) (gnomAD).

What do computational predictors say about CCT2 p.Ser458Asn (c.1373G>A)?

AlphaMissense predicts likely pathogenic (score 0.8613) — an in-silico prediction, not a clinical call.

CCT2 p.Ser458Asn

c.1373G>A · rs146372909 · VCV840493

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8613 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00638%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8613	likely pathogenic
REVEL	0.63	indeterminate
SaProt	LLR -10.51	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.3, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 4,143 bp · p 0.12 · regional, not allelic
Overall
CADD	26.2	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 0.00638% European (non-Finnish) · 75/1,176,044 alleles

Filtering AF 0.00521% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00475%

Overall 0.00505% 81/1,604,350 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00638%	15,681
Remaining individualsnot grpmax-eligible	0.00484%	20,663
African / African-American	0.00403%	24,828

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.Ser458Asn
Coding: c.1373G>A
MANE Select: NM_006431
dbSNP: rs146372909
Type: single nucleotide variant
Location: chr12:69598359 (GRCh38)
Gene constraint: LOEUF 0.445 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 89.85 · 71 PDB
Residue 458: an α-helix

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

Similar variants

CCT2 p.Ser458Gly Uncertain significance ★★ ⚠ same residue
CCT2 p.Ser458Arg 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-ser458asn (accessed [today's date]).

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