Is CCDC88C p.Arg464His (c.1391G>A) pathogenic?

CCDC88C p.Arg464His (c.1391G>A) is classified Uncertain significance in CCDC88C (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-27). AlphaMissense: likely benign (0.3107); Rare (popmax 0.333%, eas); Associated with spinocerebellar ataxia type 40.

What condition is associated with CCDC88C p.Arg464His (c.1391G>A)?

CCDC88C p.Arg464His (c.1391G>A) is associated with spinocerebellar ataxia type 40, hydrocephalus, nonsyndromic, autosomal recessive 1 (ClinVar).

How common is CCDC88C p.Arg464His (c.1391G>A) in the general population?

CCDC88C p.Arg464His (c.1391G>A) is rare (popmax 0.333%, eas) (gnomAD).

How is Spinocerebellar ataxia type 40 inherited?

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

What do computational predictors say about CCDC88C p.Arg464His (c.1391G>A)?

AlphaMissense predicts likely benign (score 0.3107) — an in-silico prediction, not a clinical call.

CCDC88C p.Arg464His

c.1391G>A · rs587782989 · VCV155879

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.3107 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.333%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

spinocerebellar ataxia type 40

Computational evidence

Protein change
AlphaMissense	0.3107	likely benign
REVEL	0.699	pathogenic-leaning
SaProt	LLR -4.51	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 1.7, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 112 kb · p 5.2e-05 · regional, not allelic
Overall
CADD	26.4	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 0.333% East Asian · 144/43,220 alleles

Filtering AF 0.289% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.272%

Overall 0.0105% 166/1,584,260 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.333%	300
Remaining individualsnot grpmax-eligible	0.00489%	20,463
Admixed American	0.00358%	27,967
European (non-Finnish)	0.00137%	72,779
African / African-American	0.00135%	74,124

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: CCDC88C
Protein: p.Arg464His
Coding: c.1391G>A
MANE Select: NM_001080414
dbSNP: rs587782989
Type: single nucleotide variant
Location: chr14:91321256 (GRCh38)
Gene constraint: LOEUF 0.759 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.69
Residue 464: a UniProt-annotated variant site (in sca40; no effect on subcellular location; increases activation of the jnk signaling pathway; induces apoptosis)

Full CCDC88C gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

spinocerebellar ataxia type 40 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hydrocephalus, nonsyndromic, autosomal recessive 1

For Spinocerebellar ataxia type 40 (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

CCDC88C p.Arg464Cys Uncertain significance ★★ ⚠ same residue
CCDC88C p.Arg464= Likely benign ★ same residue
CCDC88C c.3358-2A>C Likely pathogenic ★★ same condition
CCDC88C c.4442-2A>G Likely pathogenic ★★ same condition
CCDC88C c.4768+1G>T Likely pathogenic ★★ same condition
CCDC88C p.Arg1701Ter Pathogenic/Likely pathogenic ★★ same condition
CCDC88C p.Arg312Ter Pathogenic ★★ same condition
CCDC88C c.3358-5G>A 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/ccdc88c-p-arg464his (accessed [today's date]).

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