Is SCRIB p.Leu158= (c.474C>T) pathogenic?

SCRIB p.Leu158= (c.474C>T) is classified Benign in SCRIB (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-11-26). Common (popmax 8.69%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with SCRIB-related disorder.

What condition is associated with SCRIB p.Leu158= (c.474C>T)?

SCRIB p.Leu158= (c.474C>T) is associated with SCRIB-related disorder (ClinVar).

SCRIB p.Leu158=

Q: How common is SCRIB p.Leu158= (c.474C>T) in the general population?

SCRIB p.Leu158= (c.474C>T) is common (popmax 8.69%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.474C>T · rs56748182 · VCV3059254

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Common

common (popmax 8.69%, nfe) — 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 carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.76	GERP -3.3, phastCons 0.001
Overall
CADD	4.472	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.69% European (non-Finnish) · 102,492/1,179,924 alleles

Filtering AF 8.64% ClinGen BA1/BS1 input FAF95, joint · FAF99 8.62%

Overall 7.81% 125,976/1,613,080 alleles · common exomes 116,134/1,460,796 · genomes 9,842/152,284 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	12.3%	8
Finnishnot grpmax-eligible	11.6%	9
European (non-Finnish)grpmax	8.69%	12
Remaining individualsnot grpmax-eligible	7.53%	13
Ashkenazi Jewishnot grpmax-eligible	6.07%	16
Middle Eastern	5.83%	17
South Asian	4.68%	21
Admixed American	4.09%	24
East Asian	2.15%	47
African / African-American	2.01%	50

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: SCRIB
Protein: p.Leu158=
Coding: c.474C>T
MANE Select: NM_182706
dbSNP: rs56748182
Type: single nucleotide variant
Location: chr8:143813499 (GRCh38)
Gene constraint: LOEUF 0.684 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 52.33 · 42 PDB
Residue 158: the 'sufficient for targeting to adherens junction and to inhibit cell proliferation' region

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

Disease context

SCRIB-related disorder

Similar variants

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
SCRIB c.907-4C>T 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-leu158 (accessed [today's date]).

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