Is SCN8A p.Lys1237Arg (c.3710A>G) pathogenic?

SCN8A p.Lys1237Arg (c.3710A>G) is classified Conflicting classifications of pathogenicity in SCN8A (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-04-21). AlphaMissense: likely benign (0.1185); Very rare (popmax 0.00568%, nfe); Associated with early-infantile DEE.

What condition is associated with SCN8A p.Lys1237Arg (c.3710A>G)?

SCN8A p.Lys1237Arg (c.3710A>G) is associated with early-infantile DEE (ClinVar).

How common is SCN8A p.Lys1237Arg (c.3710A>G) in the general population?

SCN8A p.Lys1237Arg (c.3710A>G) is very rare (popmax 0.00568%, nfe) (gnomAD).

What do computational predictors say about SCN8A p.Lys1237Arg (c.3710A>G)?

AlphaMissense predicts likely benign (score 0.1185) — an in-silico prediction, not a clinical call.

SCN8A p.Lys1237Arg

c.3710A>G · rs377197765 · VCV392657

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1185 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00568%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

early-infantile DEE

Computational evidence

Protein change
AlphaMissense	0.1185	likely benign
REVEL	0.51	indeterminate
SaProt	LLR -11.71	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.3	GERP 1.9, phastCons 1
Regional constraint	o/e 0.36	unconstrained · MANE · 10 kb · p 4.2e-12 · regional, not allelic
Overall
CADD	22.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00568% European (non-Finnish) · 67/1,179,966 alleles

Filtering AF 0.00454% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00417%

Overall 0.00452% 73/1,613,966 alleles · very rare exomes 63/1,461,770 · genomes 10/152,196 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.008%	12,494
European (non-Finnish)grpmax	0.00568%	17,611
African / African-American	0.00133%	74,928

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: SCN8A
Protein: p.Lys1237Arg
Coding: c.3710A>G
MANE Select: NM_001330260
dbSNP: rs377197765
Type: single nucleotide variant
Location: chr12:51774253 (GRCh38)
Gene constraint: LOEUF 0.189 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 68.90 · 7 PDB
Residue 1237: an α-helix

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

Disease context

early-infantile DEE — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SCN8A c.615-1G>A Pathogenic ★★★ same condition
SCN8A p.Arg1872Gln 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
SCN8A p.Tyr401His 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-lys1237arg (accessed [today's date]).

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