Is CCT8L2 p.Pro333Ser (c.997C>T) pathogenic?

CCT8L2 p.Pro333Ser (c.997C>T) is classified Uncertain significance in CCT8L2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-06). AlphaMissense: likely benign (0.1221); Very rare (popmax 0.0028%, nfe).

How common is CCT8L2 p.Pro333Ser (c.997C>T) in the general population?

CCT8L2 p.Pro333Ser (c.997C>T) is very rare (popmax 0.0028%, nfe) (gnomAD).

What do computational predictors say about CCT8L2 p.Pro333Ser (c.997C>T)?

AlphaMissense predicts likely benign (score 0.1221) — an in-silico prediction, not a clinical call.

CCT8L2 p.Pro333Ser

c.997C>T · VCV3997909

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1221 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0028%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1221	likely benign
REVEL	0.118	moderately benign-leaning
SaProt	LLR -8.00	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 5.1	phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 1,670 bp · p 5.2e-05 · regional, not allelic
Overall
CADD	16.92	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 0.0028% European (non-Finnish) · 33/1,180,048 alleles

Filtering AF 0.00199% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00175%

Overall 0.00211% 34/1,614,088 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0028%	35,759
Remaining individualsnot grpmax-eligible	0.0016%	62,488

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: CCT8L2
Protein: p.Pro333Ser
Coding: c.997C>T
MANE Select: NM_014406
Type: single nucleotide variant
Location: chr22:16591554 (GRCh38)
Gene constraint: LOEUF 1.252 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.62

Full CCT8L2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCT8L2 p.Pro344Thr Benign ★★ ⚠ same type
CCT8L2 p.Ala106Asp Uncertain significance ★ ⚠ same type
CCT8L2 p.Ala106Gly Uncertain significance ★ ⚠ same type
CCT8L2 p.Ala137Thr Uncertain significance ★ ⚠ same type
CCT8L2 p.Ala141Ser Uncertain significance ★ ⚠ same type
CCT8L2 p.Ala145Thr Uncertain significance ★ ⚠ same type
CCT8L2 p.Ala151Pro Uncertain significance ★ ⚠ same type
CCT8L2 p.Ala185Asp 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/cct8l2-p-pro333ser (accessed [today's date]).

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