Is CPA6 p.Phe97Ser (c.290T>C) pathogenic?

CPA6 p.Phe97Ser (c.290T>C) is classified Uncertain significance in CPA6 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-08-20). AlphaMissense: likely benign (0.3256); Very rare (popmax 0.000424%, nfe); Associated with febrile seizures, familial, 11.

What condition is associated with CPA6 p.Phe97Ser (c.290T>C)?

CPA6 p.Phe97Ser (c.290T>C) is associated with febrile seizures, familial, 11 (ClinVar).

How common is CPA6 p.Phe97Ser (c.290T>C) in the general population?

CPA6 p.Phe97Ser (c.290T>C) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about CPA6 p.Phe97Ser (c.290T>C)?

AlphaMissense predicts likely benign (score 0.3256) — an in-silico prediction, not a clinical call.

CPA6 p.Phe97Ser

c.290T>C · rs372902713 · VCV574209

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3256 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

febrile seizures, familial, 11

Computational evidence

Protein change
AlphaMissense	0.3256	likely benign
REVEL	0.133	moderately benign-leaning
SaProt	LLR -4.65	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 9.4	GERP 2.1, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 324 kb · p 0.094 · regional, not allelic
Overall
CADD	21.8	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 0.000424% European (non-Finnish) · 5/1,179,462 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.00031% 5/1,612,354 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.Phe97Ser
Coding: c.290T>C
MANE Select: NM_020361
dbSNP: rs372902713
Type: single nucleotide variant
Location: chr8:67517950 (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.Phe97Leu 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-phe97ser (accessed [today's date]).

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