Is SCRIB p.Arg1366= (c.4098C>T) pathogenic?

SCRIB p.Arg1366= (c.4098C>T) is classified Benign in SCRIB (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-10-28). Common (popmax 6.66%, eas) — too common for a highly-penetrant pathogenic allele; Associated with SCRIB-related disorder.

What condition is associated with SCRIB p.Arg1366= (c.4098C>T)?

SCRIB p.Arg1366= (c.4098C>T) is associated with SCRIB-related disorder (ClinVar).

SCRIB p.Arg1366=

Q: How common is SCRIB p.Arg1366= (c.4098C>T) in the general population?

SCRIB p.Arg1366= (c.4098C>T) is common (popmax 6.66%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.4098C>T · rs72693351 · VCV3059816

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Common

common (popmax 6.66%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

SCRIB-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
REVEL	0.066	moderately benign-leaning
Splicing
SpliceAI	Δ0.33	donor gain · deltas
Constraint at this position
Conservation	phyloP -0.12	GERP -2.9
Overall
CADD	13.83	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.66% East Asian · 2,953/44,328 alleles

Filtering AF 6.46% ClinGen BA1/BS1 input FAF95, joint · FAF99 6.38%

Overall 2.81% 44,401/1,578,838 alleles · common exomes 40,550/1,426,576 · genomes 3,851/152,262 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	7.96%	13
East Asiangrpmax	6.66%	15
South Asian	5.86%	17
Remaining individualsnot grpmax-eligible	2.79%	36
European (non-Finnish)	2.43%	41
Ashkenazi Jewishnot grpmax-eligible	2.04%	49
Middle Eastern	1.65%	60
Admixed American	1.21%	83
African / African-American	0.732%	137

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: SCRIB
Protein: p.Arg1366=
Coding: c.4098C>T
MANE Select: NM_182706
dbSNP: rs72693351
Type: single nucleotide variant
Location: chr8:143792787 (GRCh38)
Gene constraint: LOEUF 0.684 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 52.33 · 42 PDB
Residue 1366: the 'disordered' region

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

Disease context

SCRIB-related disorder

Similar variants

SCRIB p.Arg1366His Uncertain significance ★ ⚠ same residue
SCRIB p.Arg231Gln Uncertain significance ★ ⚠ same condition
SCRIB c.2179-10C>T Likely benign same condition
SCRIB c.3714+7G>A Likely benign same condition
SCRIB c.4018-6C>T Likely benign same condition
SCRIB c.4514+8C>T Likely benign same condition
SCRIB c.4515-4G>A Likely benign same condition
SCRIB c.907-4C>G Likely benign 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/scrib-p-arg1366 (accessed [today's date]).

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