Is SCRIB p.Arg1152His (c.3455G>A) pathogenic?

SCRIB p.Arg1152His (c.3455G>A) is classified Uncertain significance in SCRIB (ClinVar, Single submitter, 3 submitters; last evaluated 2025-08-21). AlphaMissense: likely benign (0.0885); Rare (popmax 0.828%, afr).

How common is SCRIB p.Arg1152His (c.3455G>A) in the general population?

SCRIB p.Arg1152His (c.3455G>A) is rare (popmax 0.828%, afr) (gnomAD).

What do computational predictors say about SCRIB p.Arg1152His (c.3455G>A)?

AlphaMissense predicts likely benign (score 0.0885) — an in-silico prediction, not a clinical call.

SCRIB p.Arg1152His

c.3455G>A · rs140946440 · VCV3038738

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0885 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.828%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0885	likely benign
REVEL	0.039	moderately benign-leaning
SaProt	LLR -9.79	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 1.1	GERP 0.23, phastCons 0.13
Regional constraint	o/e 1.13	unconstrained · MANE · 20 kb · p 9.1e-08 · regional, not allelic
Overall
CADD	19.43	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 0.828% African / African-American · 621/74,966 alleles

Filtering AF 0.774% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.753%

Overall 0.0418% 670/1,604,220 alleles · rare exomes 328/1,452,158 · genomes 342/152,062 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.828%	121
Middle Eastern	0.0334%	2,997
Admixed American	0.0317%	3,153
Remaining individualsnot grpmax-eligible	0.0273%	3,667
East Asian	0.00223%	44,808
South Asian	0.0011%	90,934
European (non-Finnish)	0.000763%	131,032

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.Arg1152His
Coding: c.3455G>A
MANE Select: NM_182706
dbSNP: rs140946440
Type: single nucleotide variant
Location: chr8:143803531 (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.Arg1152Cys 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-arg1152his (accessed [today's date]).

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