Is SCRIB p.Arg867Cys (c.2599C>T) pathogenic?

SCRIB p.Arg867Cys (c.2599C>T) is classified Uncertain significance in SCRIB (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-10). AlphaMissense: likely pathogenic (0.7421); Ultra-rare (popmax 0.028%, sas).

How common is SCRIB p.Arg867Cys (c.2599C>T) in the general population?

SCRIB p.Arg867Cys (c.2599C>T) is ultra-rare (popmax 0.028%, sas) (gnomAD).

What do computational predictors say about SCRIB p.Arg867Cys (c.2599C>T)?

AlphaMissense predicts likely pathogenic (score 0.7421) — an in-silico prediction, not a clinical call.

SCRIB p.Arg867Cys

c.2599C>T · VCV3793321

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7421 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.028%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.7421	likely pathogenic
REVEL	0.328	indeterminate
SaProt	LLR -14.50	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6.4	GERP 0.42, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 20 kb · p 9.1e-08 · regional, not allelic
Overall
CADD	26.2	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 0.028% South Asian · 24/85,734 alleles

Filtering AF 0.0193% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0163%

Overall 0.00292% 46/1,576,264 alleles · ultra-rare exomes 41/1,424,142 · genomes 5/152,122 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.028%	3,572
Admixed American	0.00707%	14,143
Remaining individualsnot grpmax-eligible	0.00494%	20,246
Finnishnot grpmax-eligible	0.0034%	29,406
East Asian	0.00226%	44,302
European (non-Finnish)	0.00103%	96,823

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.Arg867Cys
Coding: c.2599C>T
MANE Select: NM_182706
Type: single nucleotide variant
Location: chr8:143805183 (GRCh38)
Gene constraint: LOEUF 0.684 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 52.33 · 42 PDB
Residue 867: the pdz 2 domain; 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-arg867cys (accessed [today's date]).

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