Is CCT4 p.Cys252Trp (c.756C>G) pathogenic?

CCT4 p.Cys252Trp (c.756C>G) is classified Uncertain significance in CCT4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-27). AlphaMissense: likely pathogenic (0.9866); Very rare (popmax 0.00237%, nfe).

How common is CCT4 p.Cys252Trp (c.756C>G) in the general population?

CCT4 p.Cys252Trp (c.756C>G) is very rare (popmax 0.00237%, nfe) (gnomAD).

What do computational predictors say about CCT4 p.Cys252Trp (c.756C>G)?

AlphaMissense predicts likely pathogenic (score 0.9866) — an in-silico prediction, not a clinical call.

CCT4 p.Cys252Trp

c.756C>G · VCV3997867

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9866 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00237%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9866	likely pathogenic
REVEL	0.813	moderately pathogenic-leaning
SaProt	LLR -15.13	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 0.56	GERP -3.3, phastCons 0.99
Regional constraint	o/e 0.91	unconstrained · MANE · 15 kb · p 0.04 · regional, not allelic
Overall
CADD	22.3	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 0.00237% European (non-Finnish) · 28/1,179,544 alleles

Filtering AF 0.00165% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00142%

Overall 0.0018% 29/1,612,608 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00237%	42,127
Remaining individualsnot grpmax-eligible	0.0016%	62,408

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: CCT4
Protein: p.Cys252Trp
Coding: c.756C>G
MANE Select: NM_006430
Type: single nucleotide variant
Location: chr2:61876941 (GRCh38)
Gene constraint: LOEUF 0.647 · pLI 0.70 (gnomAD)
Structure: AlphaFold pLDDT 90.05 · 72 PDB

Full CCT4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCT4 p.Ala113Gly Uncertain significance ★ ⚠ same type
CCT4 p.Ala113Val Uncertain significance ★ ⚠ same type
CCT4 p.Ala308Val Uncertain significance ★ ⚠ same type
CCT4 p.Ala408Ser Uncertain significance ★ ⚠ same type
CCT4 p.Ala41Thr Uncertain significance ★ ⚠ same type
CCT4 p.Ala518Ser Uncertain significance ★ ⚠ same type
CCT4 p.Arg274Gln Uncertain significance ★ ⚠ same type
CCT4 p.Arg441Pro 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/cct4-p-cys252trp (accessed [today's date]).

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