Is CCT8 p.Val409Ile (c.1225G>A) pathogenic?

CCT8 p.Val409Ile (c.1225G>A) is classified Benign in CCT8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-05-18). AlphaMissense: likely benign (0.1069); Common (popmax 7.27%, afr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about CCT8 p.Val409Ile (c.1225G>A)?

AlphaMissense predicts likely benign (score 0.1069) — an in-silico prediction, not a clinical call.

CCT8 p.Val409Ile

Q: How common is CCT8 p.Val409Ile (c.1225G>A) in the general population?

CCT8 p.Val409Ile (c.1225G>A) is common (popmax 7.27%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1225G>A · rs8129954 · VCV769121

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1069 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 7.27%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1069	likely benign
REVEL	0.244	benign-leaning
SaProt	LLR -3.94	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 2.7	GERP -0.039, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 17 kb · p 9.2e-05 · regional, not allelic
Overall
CADD	21.7	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 7.27% African / African-American · 5,445/74,910 alleles

Filtering AF 7.11% ClinGen BA1/BS1 input FAF95, joint · FAF99 7.04%

Overall 0.396% 6,391/1,613,258 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	7.27%	14
Middle Eastern	0.545%	183
Remaining individualsnot grpmax-eligible	0.512%	195
Admixed American	0.483%	207
European (non-Finnish)	0.0242%	4,138
South Asian	0.0176%	5,691
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,590
Finnishnot grpmax-eligible	0.00156%	63,962

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: CCT8
Protein: p.Val409Ile
Coding: c.1225G>A
MANE Select: NM_006585
dbSNP: rs8129954
Type: single nucleotide variant
Location: chr21:29061555 (GRCh38)
Gene constraint: LOEUF 0.287 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 87.85 · 71 PDB
Residue 409: a UniProt-annotated variant site (in); a β-strand

Full CCT8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCT8 p.Ala12Thr Uncertain significance ★ ⚠ same type
CCT8 p.Ala186Thr Uncertain significance ★ ⚠ same type
CCT8 p.Ala298Thr Uncertain significance ★ ⚠ same type
CCT8 p.Ala35Thr Uncertain significance ★ ⚠ same type
CCT8 p.Ala442Gly Uncertain significance ★ ⚠ same type
CCT8 p.Ala447Val Uncertain significance ★ ⚠ same type
CCT8 p.Ala451Thr Uncertain significance ★ ⚠ same type
CCT8 p.Ala451Val 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/cct8-p-val409ile (accessed [today's date]).

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