Is CPA6 p.Ser77Ter (c.230C>G) pathogenic?

CPA6 p.Ser77Ter (c.230C>G) is classified Likely pathogenic in CPA6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-01). Very rare (popmax 0.00017%, nfe); Associated with febrile seizures, familial, 11.

What condition is associated with CPA6 p.Ser77Ter (c.230C>G)?

CPA6 p.Ser77Ter (c.230C>G) is associated with febrile seizures, familial, 11 (ClinVar).

How common is CPA6 p.Ser77Ter (c.230C>G) in the general population?

CPA6 p.Ser77Ter (c.230C>G) is very rare (popmax 0.00017%, nfe) (gnomAD).

CPA6 p.Ser77Ter

c.230C>G · VCV4813838

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Conditions

febrile seizures, familial, 11

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 3 of 11
Splicing
SpliceAI	Δ0.20	acceptor loss · deltas
Pangolin	Δ0.31	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Overall
CADD	38.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,179,226 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,459,532 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.Ser77Ter
Coding: c.230C>G
MANE Select: NM_020361
Type: single nucleotide variant
Location: chr8:67518010 (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

febrile seizures, familial, 11 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CPA6 p.Ser77Thr Uncertain significance ★ ⚠ same residue
CPA6 c.534+4A>G Uncertain significance ★★ same condition
CPA6 p.Arg128Ter Uncertain significance ★★ same condition
CPA6 p.Arg182Gln Uncertain significance ★★ ⚠ same condition
CPA6 p.Arg36Leu Uncertain significance ★★ ⚠ same condition
CPA6 p.Arg7His Uncertain significance ★★ ⚠ same condition
CPA6 p.Arg92Gln Uncertain significance ★★ ⚠ same condition
CPA6 p.Asn35Lys 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-ser77ter (accessed [today's date]).

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