Is SCRIB p.Arg762Trp (c.2284C>T) pathogenic?

SCRIB p.Arg762Trp (c.2284C>T) is classified Uncertain significance in SCRIB (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-16). AlphaMissense: likely pathogenic (0.8846); Very rare (popmax 0.00511%, amr).

How common is SCRIB p.Arg762Trp (c.2284C>T) in the general population?

SCRIB p.Arg762Trp (c.2284C>T) is very rare (popmax 0.00511%, amr) (gnomAD).

What do computational predictors say about SCRIB p.Arg762Trp (c.2284C>T)?

AlphaMissense predicts likely pathogenic (score 0.8846) — an in-silico prediction, not a clinical call.

SCRIB p.Arg762Trp

c.2284C>T · rs782384815 · VCV2278518

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8846 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00511%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.8846	likely pathogenic
REVEL	0.452	indeterminate
SaProt	LLR -15.80	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.80 · evaluated, not missing
Constraint at this position
Conservation	phyloP 8.6	GERP 1.5, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 20 kb · p 9.1e-08 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00511% Admixed American · 3/58,714 alleles

Filtering AF 0.00136% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000676%

Overall 0.000563% 9/1,599,448 alleles · very rare exomes 9/1,447,138 · genomes 0/152,310 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00511%	19,571
Ashkenazi Jewishnot grpmax-eligible	0.00341%	29,302
East Asian	0.00226%	44,208
Remaining individualsnot grpmax-eligible	0.00162%	61,884
European (non-Finnish)	0.000256%	390,885

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.Arg762Trp
Coding: c.2284C>T
MANE Select: NM_182706
dbSNP: rs782384815
Type: single nucleotide variant
Location: chr8:143806469 (GRCh38)
Gene constraint: LOEUF 0.684 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 52.33 · 42 PDB
Residue 762: a β-strand; the pdz 1 domain; the 'sufficient for targeting to adherens junction and to inhibit cell proliferation' region; the 'interaction with arhgef7' region; the 'required for interaction with vim' 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-arg762trp (accessed [today's date]).

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