Is CCT5 p.Met4Val (c.10A>G) pathogenic?

CCT5 p.Met4Val (c.10A>G) is classified Conflicting classifications of pathogenicity in CCT5 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-07-27). AlphaMissense: likely benign (0.0636); Very rare (popmax 0.00549%, sas); Associated with hereditary sensory and autonomic neuropathy with spastic paraplegia.

What condition is associated with CCT5 p.Met4Val (c.10A>G)?

CCT5 p.Met4Val (c.10A>G) is associated with hereditary sensory and autonomic neuropathy with spastic paraplegia (ClinVar).

How common is CCT5 p.Met4Val (c.10A>G) in the general population?

CCT5 p.Met4Val (c.10A>G) is very rare (popmax 0.00549%, sas) (gnomAD).

What do computational predictors say about CCT5 p.Met4Val (c.10A>G)?

AlphaMissense predicts likely benign (score 0.0636) — an in-silico prediction, not a clinical call.

CCT5 p.Met4Val

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.10A>G · rs1281493996 · VCV1402611

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0636 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00549%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary sensory and autonomic neuropathy with spastic paraplegia

Computational evidence

Protein change
AlphaMissense	0.0636	likely benign
REVEL	0.024	moderately benign-leaning
SaProt	LLR -6.58	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.5	GERP 0.77, phastCons 0.9
Regional constraint	o/e 0.75	unconstrained · MANE · 5,706 bp · p 0.00087 · regional, not allelic
Overall
CADD	12.62	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 0.00549% South Asian · 5/91,084 alleles

Filtering AF 0.0021% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00136%

Overall 0.000744% 12/1,613,970 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00549%	18,217
African / African-American	0.00267%	37,472
East Asian	0.00223%	44,890
Admixed American	0.00167%	60,006
European (non-Finnish)	0.000254%	393,345

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.Met4Val
Coding: c.10A>G
MANE Select: NM_012073
dbSNP: rs1281493996
Type: single nucleotide variant
Location: chr5:10250350 (GRCh38)
Gene constraint: LOEUF 0.235 · pLI 1.00 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 89.34 · 75 PDB

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-met4val (accessed [today's date]).

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