Is CCT5 p.Ala398= (c.1194G>A) pathogenic?

CCT5 p.Ala398= (c.1194G>A) is classified Benign/Likely benign in CCT5 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-15). Low-frequency (popmax 2.46%, afr); Associated with hereditary sensory and autonomic neuropathy with spastic paraplegia.

What condition is associated with CCT5 p.Ala398= (c.1194G>A)?

CCT5 p.Ala398= (c.1194G>A) is associated with hereditary sensory and autonomic neuropathy with spastic paraplegia (ClinVar).

How common is CCT5 p.Ala398= (c.1194G>A) in the general population?

CCT5 p.Ala398= (c.1194G>A) is low-frequency (popmax 2.46%, afr) (gnomAD).

CCT5 p.Ala398=

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.1194G>A · rs113262482 · VCV465404

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

low-frequency (popmax 2.46%, afr)

Conditions

hereditary sensory and autonomic neuropathy with spastic paraplegia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.2	GERP -5.3
Overall
CADD	5.488	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.46% African / African-American · 1,846/75,034 alleles

Filtering AF 2.37% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.33%

Overall 0.148% 2,386/1,614,090 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.46%	41
Amishnot grpmax-eligible	0.329%	304
Middle Eastern	0.283%	353
Remaining individualsnot grpmax-eligible	0.234%	428
Admixed American	0.233%	429
European (non-Finnish)	0.0192%	5,221
South Asian	0.00549%	18,215
Finnishnot grpmax-eligible	0.00312%	32,016
East Asian	0.00223%	44,886

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.Ala398=
Coding: c.1194G>A
MANE Select: NM_012073
dbSNP: rs113262482
Type: single nucleotide variant
Location: chr5:10262495 (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 398: 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-ala398 (accessed [today's date]).

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