Is SCRIB p.Arg346His (c.1037G>A) pathogenic?

SCRIB p.Arg346His (c.1037G>A) is classified Uncertain significance in SCRIB (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-03). AlphaMissense: likely benign (0.0895); Very rare (popmax 0.00836%, amr).

How common is SCRIB p.Arg346His (c.1037G>A) in the general population?

SCRIB p.Arg346His (c.1037G>A) is very rare (popmax 0.00836%, amr) (gnomAD).

What do computational predictors say about SCRIB p.Arg346His (c.1037G>A)?

AlphaMissense predicts likely benign (score 0.0895) — an in-silico prediction, not a clinical call.

SCRIB p.Arg346His

c.1037G>A · rs202086187 · VCV3158661

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0895 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00836%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.0895	likely benign
REVEL	0.441	indeterminate
SaProt	LLR -9.06	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	GERP 0.3, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 4,447 bp · p 0.0026 · regional, not allelic
Overall
CADD	28.3	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 0.00836% Admixed American · 5/59,816 alleles

Filtering AF 0.00579% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00533%

Overall 0.00577% 93/1,611,344 alleles · very rare exomes 87/1,459,132 · genomes 6/152,212 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00836%	11,963
European (non-Finnish)	0.00704%	14,210
African / African-American	0.00401%	24,963
Remaining individualsnot grpmax-eligible	0.00321%	31,174

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.Arg346His
Coding: c.1037G>A
MANE Select: NM_182706
dbSNP: rs202086187
Type: single nucleotide variant
Location: chr8:143811215 (GRCh38)
Gene constraint: LOEUF 0.684 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 52.33 · 42 PDB
Residue 346: the 'sufficient for targeting to adherens junction and to inhibit cell proliferation' region

Full SCRIB gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SCRIB p.Arg346Cys Uncertain significance ★ ⚠ 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
SCRIB p.Phe571= 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-arg346his (accessed [today's date]).

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