Is CCT4 p.Lys143Arg (c.428A>G) pathogenic?

CCT4 p.Lys143Arg (c.428A>G) is classified Uncertain significance in CCT4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-30). AlphaMissense: likely benign (0.0959); Very rare (popmax 0.00677%, amr).

How common is CCT4 p.Lys143Arg (c.428A>G) in the general population?

CCT4 p.Lys143Arg (c.428A>G) is very rare (popmax 0.00677%, amr) (gnomAD).

What do computational predictors say about CCT4 p.Lys143Arg (c.428A>G)?

AlphaMissense predicts likely benign (score 0.0959) — an in-silico prediction, not a clinical call.

CCT4 p.Lys143Arg

c.428A>G · VCV4222388

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0959 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00677%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0959	likely benign
REVEL	0.407	indeterminate
SaProt	LLR -8.16	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.89	GERP 1.4, phastCons 0.85
Regional constraint	o/e 0.91	unconstrained · MANE · 15 kb · p 0.04 · regional, not allelic
Overall
CADD	22.2	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 0.00677% Admixed American · 4/59,122 alleles

Filtering AF 0.00228% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00136%

Overall 0.00112% 18/1,608,852 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00677%	14,781
African / African-American	0.00134%	74,808
European (non-Finnish)	0.0011%	90,526

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.Lys143Arg
Coding: c.428A>G
MANE Select: NM_006430
Type: single nucleotide variant
Location: chr2:61878963 (GRCh38)
Gene constraint: LOEUF 0.647 · pLI 0.70 (gnomAD)
Structure: AlphaFold pLDDT 90.05 · 72 PDB
Residue 143: an α-helix

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-lys143arg (accessed [today's date]).

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