Is SCN11A p.Pro545= (c.1635T>C) pathogenic?

SCN11A p.Pro545= (c.1635T>C) is classified Likely benign in SCN11A (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-03). Very rare (popmax 0.000342%, nfe); Associated with hereditary sensory and autonomic neuropathy type 7.

What condition is associated with SCN11A p.Pro545= (c.1635T>C)?

SCN11A p.Pro545= (c.1635T>C) is associated with hereditary sensory and autonomic neuropathy type 7, familial episodic pain syndrome with predominantly lower limb involvement (ClinVar).

How common is SCN11A p.Pro545= (c.1635T>C) in the general population?

SCN11A p.Pro545= (c.1635T>C) is very rare (popmax 0.000342%, nfe) (gnomAD).

SCN11A p.Pro545=

Q: How is Hereditary sensory and autonomic neuropathy type 7 inherited?

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

c.1635T>C · rs769313990 · VCV1901971

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000342%, nfe)

Conditions

hereditary sensory and autonomic neuropathy type 7

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 -8.8	GERP -5.5
Overall
CADD	0.674	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000342% European (non-Finnish) · 4/1,170,486 alleles

Filtering AF 8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000251% 4/1,591,208 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: SCN11A
Protein: p.Pro545=
Coding: c.1635T>C
MANE Select: NM_001349253
dbSNP: rs769313990
Type: single nucleotide variant
Location: chr3:38904072 (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

hereditary sensory and autonomic neuropathy type 7 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial episodic pain syndrome with predominantly lower limb involvement

For Hereditary sensory and autonomic neuropathy type 7 (Orphanet):

Inheritance: Autosomal dominant
Onset: Infancy, Neonatal

Similar variants

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
SCN11A c.4327+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/scn11a-p-pro545 (accessed [today's date]).

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