Is CCT5 p.Ala424Ser (c.1270G>T) pathogenic?

CCT5 p.Ala424Ser (c.1270G>T) is classified Uncertain significance in CCT5 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-04-22). AlphaMissense: likely benign (0.1093); Ultra-rare (popmax 0.0445%, eas); Associated with hereditary sensory and autonomic neuropathy with spastic paraplegia.

What condition is associated with CCT5 p.Ala424Ser (c.1270G>T)?

CCT5 p.Ala424Ser (c.1270G>T) is associated with hereditary sensory and autonomic neuropathy with spastic paraplegia (ClinVar).

How common is CCT5 p.Ala424Ser (c.1270G>T) in the general population?

CCT5 p.Ala424Ser (c.1270G>T) is ultra-rare (popmax 0.0445%, eas) (gnomAD).

What do computational predictors say about CCT5 p.Ala424Ser (c.1270G>T)?

AlphaMissense predicts likely benign (score 0.1093) — an in-silico prediction, not a clinical call.

CCT5 p.Ala424Ser

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.1270G>T · rs767982457 · VCV905599

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1093 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0445%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary sensory and autonomic neuropathy with spastic paraplegia

Computational evidence

Protein change
AlphaMissense	0.1093	likely benign
REVEL	0.404	indeterminate
SaProt	LLR -8.67	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 10	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	23.2	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 0.0445% East Asian · 20/44,896 alleles

Filtering AF 0.0295% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0246%

Overall 0.00204% 33/1,614,140 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0445%	2,245
Remaining individualsnot grpmax-eligible	0.0032%	31,245
Admixed American	0.00167%	60,016
African / African-American	0.00133%	74,954
South Asian	0.0011%	91,090
European (non-Finnish)	0.000678%	147,506

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.Ala424Ser
Coding: c.1270G>T
MANE Select: NM_012073
dbSNP: rs767982457
Type: single nucleotide variant
Location: chr5:10262571 (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 424: 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.Arg142Cys Uncertain significance ★★ ⚠ same condition
CCT5 p.Arg400Leu Uncertain significance ★★ ⚠ same condition
CCT5 p.Arg417His 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-ala424ser (accessed [today's date]).

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