Is SCRIB p.Arg1357Gln (c.4070G>A) pathogenic?

SCRIB p.Arg1357Gln (c.4070G>A) is classified Uncertain significance in SCRIB (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-20). AlphaMissense: likely pathogenic (0.6196); Very rare (popmax 0.00545%, amr).

How common is SCRIB p.Arg1357Gln (c.4070G>A) in the general population?

SCRIB p.Arg1357Gln (c.4070G>A) is very rare (popmax 0.00545%, amr) (gnomAD).

What do computational predictors say about SCRIB p.Arg1357Gln (c.4070G>A)?

AlphaMissense predicts likely pathogenic (score 0.6196) — an in-silico prediction, not a clinical call.

SCRIB p.Arg1357Gln

c.4070G>A · VCV4581366

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6196 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00545%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6196	likely pathogenic
REVEL	0.135	moderately benign-leaning
SaProt	LLR -9.36	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.8	GERP -1.2, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 20 kb · p 9.1e-08 · regional, not allelic
Overall
CADD	23.8	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 0.00545% Admixed American · 3/55,020 alleles

Filtering AF 0.00193% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00168%

Overall 0.00315% 49/1,554,766 alleles · very rare exomes 47/1,402,576 · genomes 2/152,190 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0116%	8,590
Finnishnot grpmax-eligible	0.00551%	18,161
Admixed Americangrpmax	0.00545%	18,340
South Asian	0.00484%	20,641
European (non-Finnish)	0.00269%	37,165
African / African-American	0.00136%	73,638

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg1357Gln
Coding: c.4070G>A
MANE Select: NM_182706
Type: single nucleotide variant
Location: chr8:143792815 (GRCh38)
Gene constraint: LOEUF 0.684 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 52.33 · 42 PDB
Residue 1357: 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-arg1357gln (accessed [today's date]).

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