Is SCN8A p.Pro1824= (c.5472C>A) pathogenic?

SCN8A p.Pro1824= (c.5472C>A) is classified Benign in SCN8A (ClinVar, Multiple submitters, 15 submitters; last evaluated 2026-02-04). Common (popmax 75.2%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with Inborn genetic diseases.

What condition is associated with SCN8A p.Pro1824= (c.5472C>A)?

SCN8A p.Pro1824= (c.5472C>A) is associated with Inborn genetic diseases, cognitive impairment with or without cerebellar ataxia, developmental and epileptic encephalopathy, 13 (ClinVar).

SCN8A p.Pro1824=

Q: How common is SCN8A p.Pro1824= (c.5472C>A) in the general population?

SCN8A p.Pro1824= (c.5472C>A) is common (popmax 75.2%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.5472C>A · rs60637 · VCV130251

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 15 submitters

gnomAD v4.1

Common

common (popmax 75.2%, nfe) — too common for a highly-penetrant pathogenic allele

Conditions

Inborn genetic diseases

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 0.62	GERP -2.8, phastCons 1
Overall
CADD	6.439	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 75.2% European (non-Finnish) · 887,697/1,179,802 alleles

Filtering AF 75.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 75.1%

Overall 69.8% 1,125,606/1,613,622 alleles · common exomes 1,033,975/1,461,630 · genomes 91,631/151,992 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	81.6%	1
European (non-Finnish)grpmax	75.2%	1
Admixed American	73.4%	1
Finnishnot grpmax-eligible	72.8%	1
Remaining individualsnot grpmax-eligible	68.4%	1
Ashkenazi Jewishnot grpmax-eligible	67.6%	1
Middle Eastern	61.8%	2
East Asian	53.4%	2
South Asian	37%	3
African / African-American	30%	3

Amish 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: SCN8A
Protein: p.Pro1824=
Coding: c.5472C>A
MANE Select: NM_001330260
dbSNP: rs60637
Type: single nucleotide variant
Location: chr12:51806958 (GRCh38)
Gene constraint: LOEUF 0.189 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 68.90 · 7 PDB

Full SCN8A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: cognitive impairment with or without cerebellar ataxia developmental and epileptic encephalopathy, 13 seizures, benign familial infantile, 5 myoclonus, familial, 2 early-infantile DEE

Similar variants

SCN8A c.615-1G>A Pathogenic ★★★ same condition
SCN8A p.Arg1872Gln Pathogenic ★★★ ⚠ same condition
SCN8A p.Asn1318Ser Likely pathogenic ★★★ same condition
SCN8A p.Asn418Asp Likely pathogenic ★★★ same condition
SCN8A p.Glu1218Lys Pathogenic ★★★ same condition
SCN8A p.Ile1631Thr Likely pathogenic ★★★ same condition
SCN8A p.Ser845Cys Likely pathogenic ★★★ ⚠ same condition
SCN8A p.Ser845Phe Likely pathogenic ★★★ ⚠ 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/scn8a-p-pro1824 (accessed [today's date]).

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