Is SCN11A p.Pro63= (c.189C>T) pathogenic?

SCN11A p.Pro63= (c.189C>T) is classified Likely benign in SCN11A (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-19). Very rare (popmax 0.000424%, nfe); Associated with familial episodic pain syndrome with predominantly lower limb involvement.

How common is SCN11A p.Pro63= (c.189C>T) in the general population?

SCN11A p.Pro63= (c.189C>T) is very rare (popmax 0.000424%, nfe) (gnomAD).

How is Familial episodic pain syndrome inherited?

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

SCN11A p.Pro63=

Q: What condition is associated with SCN11A p.Pro63= (c.189C>T)?

SCN11A p.Pro63= (c.189C>T) is associated with familial episodic pain syndrome with predominantly lower limb involvement, hereditary sensory and autonomic neuropathy type 7 (ClinVar).

c.189C>T · rs975364189 · VCV2928285

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Conditions

familial episodic pain syndrome with predominantly lower limb involvement

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.024	GERP -5.2, phastCons 0.31
Overall
CADD	5.693	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000424% European (non-Finnish) · 5/1,179,842 alleles

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

Overall 0.000479% 7/1,461,818 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,484
Finnishnot grpmax-eligible	0.00157%	63,646
European (non-Finnish)grpmax	0.000424%	235,968

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: SCN11A
Protein: p.Pro63=
Coding: c.189C>T
MANE Select: NM_001349253
dbSNP: rs975364189
Type: single nucleotide variant
Location: chr3:38950174 (GRCh38)
Gene constraint: LOEUF 0.834 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.66

Full SCN11A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

familial episodic pain syndrome with predominantly lower limb involvement — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary sensory and autonomic neuropathy type 7

For Familial episodic pain syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Infancy, Neonatal
Prevalence: <1 / 1 000 000 (Europe)

Similar variants

SCN11A p.Pro63Leu Uncertain significance ★★ ⚠ same residue
SCN11A p.Arg222His Pathogenic ★★ ⚠ same condition
SCN11A p.Arg222Ser Pathogenic/Likely pathogenic ★★ same condition
SCN11A p.Arg225Cys Pathogenic/Likely pathogenic ★★ same condition
SCN11A p.Leu396Pro Pathogenic ★★ same condition
SCN11A c.1473+6T>C Uncertain significance ★★ same condition
SCN11A c.3220-6T>C Uncertain significance ★★ same condition
SCN11A c.3951+1A>G 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/scn11a-p-pro63 (accessed [today's date]).

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