Is SCN8A p.Ala607= (c.1821C>G) pathogenic?

SCN8A p.Ala607= (c.1821C>G) is classified Likely benign in SCN8A (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-07). Very rare (popmax 0.00268%, afr); Associated with early-infantile DEE.

What condition is associated with SCN8A p.Ala607= (c.1821C>G)?

SCN8A p.Ala607= (c.1821C>G) is associated with early-infantile DEE (ClinVar).

How common is SCN8A p.Ala607= (c.1821C>G) in the general population?

SCN8A p.Ala607= (c.1821C>G) is very rare (popmax 0.00268%, afr) (gnomAD).

SCN8A p.Ala607=

c.1821C>G · rs1329004407 · VCV1143012

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00268%, afr)

Conditions

early-infantile DEE

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -1.1	GERP -3.7, phastCons 0.001
Overall
CADD	7.45	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00268% African / African-American · 2/74,620 alleles

Filtering AF 0.000445% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000167%

Overall 0.000125% 2/1,598,482 alleles · very rare exomes 0/1,446,260 · genomes 2/152,222 · joint denominator

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.Ala607=
Coding: c.1821C>G
MANE Select: NM_001330260
dbSNP: rs1329004407
Type: single nucleotide variant
Location: chr12:51721731 (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

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

Similar variants

SCN8A p.Ala607Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
SCN8A p.Ala607Ser Uncertain significance ★ ⚠ same residue
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

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-ala607 (accessed [today's date]).

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