Is CPA6 p.Pro47Arg (c.140C>G) pathogenic?

CPA6 p.Pro47Arg (c.140C>G) is classified Uncertain significance in CPA6 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-13). AlphaMissense: likely pathogenic (0.7478); Very rare (popmax 0.00137%, afr); Associated with familial temporal lobe epilepsy 5.

What condition is associated with CPA6 p.Pro47Arg (c.140C>G)?

CPA6 p.Pro47Arg (c.140C>G) is associated with familial temporal lobe epilepsy 5 (ClinVar).

How common is CPA6 p.Pro47Arg (c.140C>G) in the general population?

CPA6 p.Pro47Arg (c.140C>G) is very rare (popmax 0.00137%, afr) (gnomAD).

How is Familial mesial temporal lobe epilepsy inherited?

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

What do computational predictors say about CPA6 p.Pro47Arg (c.140C>G)?

AlphaMissense predicts likely pathogenic (score 0.7478) — an in-silico prediction, not a clinical call.

CPA6 p.Pro47Arg

c.140C>G · rs981686338 · VCV908439

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7478 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00137%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial temporal lobe epilepsy 5

Computational evidence

Protein change
AlphaMissense	0.7478	likely pathogenic
REVEL	0.265	benign-leaning
SaProt	LLR -15.95	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 324 kb · p 0.094 · regional, not allelic
Overall
CADD	27.7	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 0.00137% African / African-American · 1/72,978 alleles

Overall 0.000658% 1/151,866 alleles · very rare

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: CPA6
Protein: p.Pro47Arg
Coding: c.140C>G
MANE Select: NM_020361
dbSNP: rs981686338
Type: single nucleotide variant
Location: chr8:67624228 (GRCh38)
Gene constraint: LOEUF 1.338 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 90.93

Full CPA6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

familial temporal lobe epilepsy 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Familial mesial temporal lobe epilepsy (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult

Similar variants

CPA6 c.534+4A>G Uncertain significance ★★ same condition
CPA6 p.Arg128Ter Uncertain significance ★★ same condition
CPA6 p.Arg36Leu Uncertain significance ★★ ⚠ same condition
CPA6 p.Arg7His Uncertain significance ★★ ⚠ same condition
CPA6 p.Gly194Asp Uncertain significance ★★ ⚠ same condition
CPA6 p.His156Tyr Uncertain significance ★★ ⚠ same condition
CPA6 p.Ile109Thr Uncertain significance ★★ ⚠ same condition
CPA6 p.Ile43Val 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/cpa6-p-pro47arg (accessed [today's date]).

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