Is SCN3A p.Pro727= (c.2181G>A) pathogenic?

SCN3A p.Pro727= (c.2181G>A) is classified Benign/Likely benign in SCN3A (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-17). Ultra-rare (popmax 0.0245%, eas).

How common is SCN3A p.Pro727= (c.2181G>A) in the general population?

SCN3A p.Pro727= (c.2181G>A) is ultra-rare (popmax 0.0245%, eas) (gnomAD).

SCN3A p.Pro727=

c.2181G>A · rs138350988 · VCV703271

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0245%, eas)

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 -0.88	GERP -5.7, phastCons 0.007
Overall
CADD	8.8	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0245% East Asian · 11/44,858 alleles

Filtering AF 0.0137% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0106%

Overall 0.00762% 123/1,613,200 alleles · ultra-rare exomes 102/1,461,072 · genomes 21/152,128 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.102%	985
East Asiangrpmax	0.0245%	4,078
African / African-American	0.0134%	7,488
European (non-Finnish)	0.00288%	34,689
Admixed American	0.00167%	59,948
Remaining individualsnot grpmax-eligible	0.0016%	62,442
South Asian	0.0011%	91,070

Finnish 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: SCN3A
Protein: p.Pro727=
Coding: c.2181G>A
MANE Select: NM_006922
dbSNP: rs138350988
Type: single nucleotide variant
Location: chr2:165138089 (GRCh38)
Gene constraint: LOEUF 0.348 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 68.76 · 2 PDB

Full SCN3A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SCN3A p.Pro727Leu Uncertain significance ★ ⚠ same residue
SCN3A p.Ile875Thr Pathogenic ★★★ same type
SCN3A p.Gly876Ser Uncertain significance ★★★ ⚠ same type
SCN3A p.Asp1803Asn Benign ★★★ same type
SCN3A p.Asp815Asn Benign ★★★ same type
SCN3A p.Gly1862Cys Benign ★★★ same type
SCN3A p.Gly900Ser Likely benign ★★★ same type
SCN3A p.Val1084Ile Benign ★★★ same type

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/scn3a-p-pro727 (accessed [today's date]).

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