Is SCN4B p.Pro26= (c.78C>G) pathogenic?

SCN4B p.Pro26= (c.78C>G) is classified Likely benign in SCN4B (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-16). Very rare (popmax 0.0011%, sas); Associated with Cardiovascular phenotype.

What condition is associated with SCN4B p.Pro26= (c.78C>G)?

SCN4B p.Pro26= (c.78C>G) is associated with Cardiovascular phenotype (ClinVar).

How common is SCN4B p.Pro26= (c.78C>G) in the general population?

SCN4B p.Pro26= (c.78C>G) is very rare (popmax 0.0011%, sas) (gnomAD).

SCN4B p.Pro26=

c.78C>G · rs1326784999 · VCV2447645

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.29	acceptor loss, 19 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP -2.6	GERP -4.1
Overall
CADD	3.366	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,070 alleles

Overall 6.2e-05% 1/1,614,072 alleles · very rare exomes 1/1,461,858 · genomes 0/152,214 · 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: SCN4B
Protein: p.Pro26=
Coding: c.78C>G
MANE Select: NM_174934
dbSNP: rs1326784999
Type: single nucleotide variant
Location: chr11:118145213 (GRCh38)
Gene constraint: LOEUF 1.324 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.91 · 5 PDB

Full SCN4B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SCN4B c.463+3A>T Uncertain significance ★★ same condition
SCN4B c.594-2A>G Uncertain significance ★★ same condition
SCN4B c.62-1G>A Uncertain significance ★★ same condition
SCN4B p.Ala12Thr Uncertain significance ★★ ⚠ same condition
SCN4B p.Arg195Trp Uncertain significance ★★ ⚠ same condition
SCN4B p.Arg67Gln Uncertain significance ★★ ⚠ same condition
SCN4B p.Asp159His Uncertain significance ★★ ⚠ same condition
SCN4B p.Gly214Val 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/scn4b-p-pro26 (accessed [today's date]).

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