Is CCT5 p.Val342Ile (c.1024G>A) pathogenic?

CCT5 p.Val342Ile (c.1024G>A) is classified Uncertain significance in CCT5 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-08). AlphaMissense: likely benign (0.1387); Very rare (popmax 0.00329%, sas); Associated with hereditary sensory and autonomic neuropathy with spastic paraplegia.

What condition is associated with CCT5 p.Val342Ile (c.1024G>A)?

CCT5 p.Val342Ile (c.1024G>A) is associated with hereditary sensory and autonomic neuropathy with spastic paraplegia (ClinVar).

How common is CCT5 p.Val342Ile (c.1024G>A) in the general population?

CCT5 p.Val342Ile (c.1024G>A) is very rare (popmax 0.00329%, sas) (gnomAD).

What do computational predictors say about CCT5 p.Val342Ile (c.1024G>A)?

AlphaMissense predicts likely benign (score 0.1387) — an in-silico prediction, not a clinical call.

CCT5 p.Val342Ile

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.1024G>A · rs777159469 · VCV2152169

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1387 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary sensory and autonomic neuropathy with spastic paraplegia

Computational evidence

Protein change
AlphaMissense	0.1387	likely benign
REVEL	0.404	indeterminate
SaProt	LLR -8.63	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.7	GERP 2.6, 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

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 0.00329% South Asian · 3/91,088 alleles

Filtering AF 0.00103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00083%

Overall 0.00149% 24/1,614,024 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00329%	30,363
Admixed American	0.00167%	59,998
European (non-Finnish)	0.00161%	62,107
Remaining individualsnot grpmax-eligible	0.0016%	62,486

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.Val342Ile
Coding: c.1024G>A
MANE Select: NM_012073
dbSNP: rs777159469
Type: single nucleotide variant
Location: chr5:10261590 (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 342: a β-strand

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-val342ile (accessed [today's date]).

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