Is SCRIB p.Pro454Leu (c.1361C>T) pathogenic?

SCRIB p.Pro454Leu (c.1361C>T) is classified Uncertain significance in SCRIB (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-10). AlphaMissense: likely benign (0.1016); Ultra-rare (popmax 0.025%, amr).

How common is SCRIB p.Pro454Leu (c.1361C>T) in the general population?

SCRIB p.Pro454Leu (c.1361C>T) is ultra-rare (popmax 0.025%, amr) (gnomAD).

What do computational predictors say about SCRIB p.Pro454Leu (c.1361C>T)?

AlphaMissense predicts likely benign (score 0.1016) — an in-silico prediction, not a clinical call.

SCRIB p.Pro454Leu

c.1361C>T · VCV3951086

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1016 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.025%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1016	likely benign
REVEL	0.139	moderately benign-leaning
SaProt	LLR -8.12	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP -0.96, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 20 kb · p 9.1e-08 · regional, not allelic
Overall
CADD	15.94	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.025% Admixed American · 15/59,916 alleles

Filtering AF 0.0154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0125%

Overall 0.000994% 16/1,608,928 alleles · ultra-rare exomes 14/1,456,754 · genomes 2/152,174 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.025%	3,994
South Asian	0.0011%	90,946

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.Pro454Leu
Coding: c.1361C>T
MANE Select: NM_182706
Type: single nucleotide variant
Location: chr8:143810729 (GRCh38)
Gene constraint: LOEUF 0.684 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 52.33 · 42 PDB
Residue 454: the 'sufficient for targeting to adherens junction and to inhibit cell proliferation' region; a UniProt-annotated variant site (in ntd; protein interactions not affected by the mutation; shows reduced protein localization to the cell membrane)

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

Similar variants

SCRIB c.3120+10C>G Benign/Likely benign ★★ same type
SCRIB c.504-9C>T Benign ★★ same type
SCRIB p.Ala1488= Likely benign ★★ same type
SCRIB p.Arg492= Benign ★★ same type
SCRIB p.Asn647= Benign/Likely benign ★★ same type
SCRIB p.Leu254= Benign ★★ same type
SCRIB p.Phe571= Benign ★★ same type
SCRIB p.Pro1343= Benign ★★ same type

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-pro454leu (accessed [today's date]).

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