Is CCT6B p.Ser49Phe (c.146C>T) pathogenic?

CCT6B p.Ser49Phe (c.146C>T) is classified Uncertain significance in CCT6B (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-12). AlphaMissense: likely pathogenic (0.7385); Very rare (popmax 0.00133%, afr).

How common is CCT6B p.Ser49Phe (c.146C>T) in the general population?

CCT6B p.Ser49Phe (c.146C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about CCT6B p.Ser49Phe (c.146C>T)?

AlphaMissense predicts likely pathogenic (score 0.7385) — an in-silico prediction, not a clinical call.

CCT6B p.Ser49Phe

c.146C>T · VCV3487693

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7385 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7385	likely pathogenic
REVEL	0.821	moderately pathogenic-leaning
SaProt	LLR -11.56	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.20	acceptor gain · deltas
Pangolin	Δ0.26	gain · loss 0.09 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 10	GERP 1.6, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 33 kb · p 0.21 · regional, not allelic
Overall
CADD	33.0	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 0.00133% African / African-American · 1/74,940 alleles

Overall 6.21e-05% 1/1,610,848 alleles · very rare exomes 0/1,458,562 · genomes 1/152,286 · joint denominator

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: CCT6B
Protein: p.Ser49Phe
Coding: c.146C>T
MANE Select: NM_006584
Type: single nucleotide variant
Location: chr17:34959642 (GRCh38)
Gene constraint: LOEUF 1.12 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.98

Full CCT6B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCT6B c.615-2A>G Benign ★★ same type
CCT6B p.Ala126Thr Uncertain significance ★ ⚠ same type
CCT6B p.Ala16Val Uncertain significance ★ ⚠ same type
CCT6B p.Ala18Val Uncertain significance ★ ⚠ same type
CCT6B p.Ala262Pro Uncertain significance ★ ⚠ same type
CCT6B p.Ala2Val Uncertain significance ★ ⚠ same type
CCT6B p.Ala390Asp Uncertain significance ★ ⚠ same type
CCT6B p.Ala433Asp 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/cct6b-p-ser49phe (accessed [today's date]).

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