Is CCT5 p.Lys293Ile (c.878A>T) pathogenic?

CCT5 p.Lys293Ile (c.878A>T) is classified Uncertain significance in CCT5 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-05-21). AlphaMissense: likely pathogenic (0.598); Very rare (popmax 0.00322%, nfe); Associated with hereditary sensory and autonomic neuropathy with spastic paraplegia.

What condition is associated with CCT5 p.Lys293Ile (c.878A>T)?

CCT5 p.Lys293Ile (c.878A>T) is associated with hereditary sensory and autonomic neuropathy with spastic paraplegia (ClinVar).

How common is CCT5 p.Lys293Ile (c.878A>T) in the general population?

CCT5 p.Lys293Ile (c.878A>T) is very rare (popmax 0.00322%, nfe) (gnomAD).

What do computational predictors say about CCT5 p.Lys293Ile (c.878A>T)?

AlphaMissense predicts likely pathogenic (score 0.598) — an in-silico prediction, not a clinical call.

CCT5 p.Lys293Ile

Q: How is Mutilating hereditary sensory neuropathy with spastic paraplegia inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.878A>T · rs148752621 · VCV350253

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.598 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00322%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary sensory and autonomic neuropathy with spastic paraplegia

Computational evidence

Protein change
AlphaMissense	0.598	likely pathogenic
REVEL	0.69	pathogenic-leaning
SaProt	LLR -8.44	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.2	GERP 2.7, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 7,066 bp · p 1.6e-09 · regional, not allelic
Overall
CADD	24.7	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 0.00322% European (non-Finnish) · 38/1,179,912 alleles

Filtering AF 0.00239% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0021%

Overall 0.0026% 42/1,613,548 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00641%	15,606
European (non-Finnish)grpmax	0.00322%	31,050

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: CCT5
Protein: p.Lys293Ile
Coding: c.878A>T
MANE Select: NM_012073
dbSNP: rs148752621
Type: single nucleotide variant
Location: chr5:10260796 (GRCh38)
Gene constraint: LOEUF 0.235 · pLI 1.00 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 89.34 · 75 PDB
Residue 293: an α-helix

Full CCT5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary sensory and autonomic neuropathy with spastic paraplegia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Mutilating hereditary sensory neuropathy with spastic paraplegia (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy

Similar variants

CCT5 c.531-3C>T Uncertain significance ★★ same condition
CCT5 c.*1126T>A Uncertain significance ★★ same condition
CCT5 c.*567G>A Uncertain significance ★★ same condition
CCT5 p.Ala246Val Uncertain significance ★★ ⚠ same condition
CCT5 p.Ala41Gly Uncertain significance ★★ ⚠ same condition
CCT5 p.Ala424Ser Uncertain significance ★★ ⚠ same condition
CCT5 p.Arg142Cys Uncertain significance ★★ ⚠ same condition
CCT5 p.Arg400Leu Uncertain significance ★★ ⚠ same condition

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/cct5-p-lys293ile (accessed [today's date]).

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