Is CCT4 p.Ile412Thr (c.1235T>C) pathogenic?

CCT4 p.Ile412Thr (c.1235T>C) is classified Uncertain significance in CCT4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-30). AlphaMissense: likely pathogenic (0.6976); Very rare (popmax 0.00223%, eas).

How common is CCT4 p.Ile412Thr (c.1235T>C) in the general population?

CCT4 p.Ile412Thr (c.1235T>C) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about CCT4 p.Ile412Thr (c.1235T>C)?

AlphaMissense predicts likely pathogenic (score 0.6976) — an in-silico prediction, not a clinical call.

CCT4 p.Ile412Thr

c.1235T>C · VCV3487672

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6976 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6976	likely pathogenic
REVEL	0.741	pathogenic-leaning
SaProt	LLR -7.06	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 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 15 kb · p 0.04 · regional, not allelic
Overall
CADD	24.4	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 0.00223% East Asian · 1/44,864 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000616% 9/1,461,130 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,864
Remaining individualsnot grpmax-eligible	0.0016%	62,484
South Asian	0.0011%	90,938
European (non-Finnish)	0.000509%	196,602

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.Ile412Thr
Coding: c.1235T>C
MANE Select: NM_006430
Type: single nucleotide variant
Location: chr2:61872479 (GRCh38)
Gene constraint: LOEUF 0.647 · pLI 0.70 (gnomAD)
Structure: AlphaFold pLDDT 90.05 · 72 PDB
Residue 412: an α-helix

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

Similar variants

CCT4 p.Ile412Val Uncertain significance ★ ⚠ same residue
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

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-ile412thr (accessed [today's date]).

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