Is SCRIB p.Arg1386Trp (c.4156C>T) pathogenic?

SCRIB p.Arg1386Trp (c.4156C>T) is classified Uncertain significance in SCRIB (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-28). AlphaMissense: ambiguous (0.4162); Ultra-rare (popmax 0.0113%, eas).

How common is SCRIB p.Arg1386Trp (c.4156C>T) in the general population?

SCRIB p.Arg1386Trp (c.4156C>T) is ultra-rare (popmax 0.0113%, eas) (gnomAD).

What do computational predictors say about SCRIB p.Arg1386Trp (c.4156C>T)?

AlphaMissense predicts ambiguous (score 0.4162) — an in-silico prediction, not a clinical call.

SCRIB p.Arg1386Trp

c.4156C>T · VCV4581373

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4162 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0113%, eas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4162	ambiguous
REVEL	0.113	moderately benign-leaning
SaProt	LLR -10.90	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.9	GERP 0.26, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 20 kb · p 9.1e-08 · regional, not allelic
Overall
CADD	26.4	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0113% East Asian · 5/44,268 alleles

Filtering AF 0.00439% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00279%

Overall 0.00277% 44/1,589,118 alleles · ultra-rare exomes 41/1,436,970 · genomes 3/152,148 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0113%	8,854
European (non-Finnish)	0.00307%	32,569
South Asian	0.00225%	44,379
Remaining individualsnot grpmax-eligible	0.00162%	61,762

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.Arg1386Trp
Coding: c.4156C>T
MANE Select: NM_182706
Type: single nucleotide variant
Location: chr8:143792729 (GRCh38)
Gene constraint: LOEUF 0.684 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 52.33 · 42 PDB
Residue 1386: the 'disordered' region

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-arg1386trp (accessed [today's date]).

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