Is SCRIB p.Arg1152Cys (c.3454C>T) pathogenic?

SCRIB p.Arg1152Cys (c.3454C>T) is classified Uncertain significance in SCRIB (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-03). AlphaMissense: likely benign (0.113); Ultra-rare (popmax 0.0175%, afr).

How common is SCRIB p.Arg1152Cys (c.3454C>T) in the general population?

SCRIB p.Arg1152Cys (c.3454C>T) is ultra-rare (popmax 0.0175%, afr) (gnomAD).

What do computational predictors say about SCRIB p.Arg1152Cys (c.3454C>T)?

AlphaMissense predicts likely benign (score 0.113) — an in-silico prediction, not a clinical call.

SCRIB p.Arg1152Cys

c.3454C>T · VCV3438430

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.113 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0175%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.113	likely benign
REVEL	0.099	moderately benign-leaning
SaProt	LLR -11.36	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2	GERP -0.8, phastCons 0.26
Regional constraint	o/e 1.13	unconstrained · MANE · 20 kb · p 9.1e-08 · regional, not allelic
Overall
CADD	20.2	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 0.0175% African / African-American · 13/74,396 alleles

Filtering AF 0.0103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00818%

Overall 0.00395% 63/1,595,616 alleles · ultra-rare exomes 56/1,445,830 · genomes 7/149,786 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0175%	5,723
Middle Eastern	0.0167%	5,996
European (non-Finnish)	0.00392%	25,538
Finnishnot grpmax-eligible	0.00185%	54,086
Admixed American	0.00168%	59,524
South Asian	0.0011%	90,682

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.Arg1152Cys
Coding: c.3454C>T
MANE Select: NM_182706
Type: single nucleotide variant
Location: chr8:143803532 (GRCh38)
Gene constraint: LOEUF 0.684 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 52.33 · 42 PDB
Residue 1152: the pdz 4 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 p.Arg1152His Uncertain significance ★ ⚠ same residue
SCRIB p.Arg1152= Likely benign ★ same residue
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

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-arg1152cys (accessed [today's date]).

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