Is CCT7 p.Leu416Phe (c.1246C>T) pathogenic?

CCT7 p.Leu416Phe (c.1246C>T) is classified Uncertain significance in CCT7 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-31). AlphaMissense: likely pathogenic (0.9327); Very rare (popmax 8.47e-05%, nfe).

How common is CCT7 p.Leu416Phe (c.1246C>T) in the general population?

CCT7 p.Leu416Phe (c.1246C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about CCT7 p.Leu416Phe (c.1246C>T)?

AlphaMissense predicts likely pathogenic (score 0.9327) — an in-silico prediction, not a clinical call.

CCT7 p.Leu416Phe

c.1246C>T · VCV4222435

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9327 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9327	likely pathogenic
REVEL	0.692	pathogenic-leaning
SaProt	LLR -13.91	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 3,687 bp · p 0.00024 · regional, not allelic
Overall
CADD	25.8	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 8.47e-05% European (non-Finnish) · 1/1,180,044 alleles

Overall 6.84e-05% 1/1,461,884 alleles · very rare

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: CCT7
Protein: p.Leu416Phe
Coding: c.1246C>T
MANE Select: NM_006429
Type: single nucleotide variant
Location: chr2:73251268 (GRCh38)
Gene constraint: LOEUF 0.455 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 89.03 · 70 PDB
Residue 416: an α-helix

Full CCT7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCT7 p.Ala101Thr Uncertain significance ★ ⚠ same type
CCT7 p.Ala182Thr Uncertain significance ★ ⚠ same type
CCT7 p.Ala299Gly Uncertain significance ★ ⚠ same type
CCT7 p.Ala502Val Uncertain significance ★ ⚠ same type
CCT7 p.Ala506Val Uncertain significance ★ ⚠ same type
CCT7 p.Ala510Val Uncertain significance ★ ⚠ same type
CCT7 p.Arg126Cys Uncertain significance ★ ⚠ same type
CCT7 p.Arg344Gln 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/cct7-p-leu416phe (accessed [today's date]).

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