Is SCRIB p.Arg1647His (c.4940G>A) pathogenic?

SCRIB p.Arg1647His (c.4940G>A) is classified Uncertain significance in SCRIB (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-31). AlphaMissense: ambiguous (0.3858); Ultra-rare (popmax 0.0265%, amr).

How common is SCRIB p.Arg1647His (c.4940G>A) in the general population?

SCRIB p.Arg1647His (c.4940G>A) is ultra-rare (popmax 0.0265%, amr) (gnomAD).

What do computational predictors say about SCRIB p.Arg1647His (c.4940G>A)?

AlphaMissense predicts ambiguous (score 0.3858) — an in-silico prediction, not a clinical call.

SCRIB p.Arg1647His

c.4940G>A · rs540090572 · VCV2456709

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3858 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0265%, amr)

Computational evidence

Protein change
AlphaMissense	0.3858	ambiguous
REVEL	0.19	benign-leaning
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.3	GERP 0.25, phastCons 1
Regional constraint	o/e 0.59	unconstrained · MANE · 57 bp · p 0.011 · regional, not allelic
Overall
CADD	23.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R1622H vs ClinVar R1647H) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0265% Admixed American · 9/33,960 alleles

Filtering AF 0.0138% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0103%

Overall 0.00278% 40/1,438,780 alleles · ultra-rare exomes 31/1,286,592 · genomes 9/152,188 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0265%	3,773
Ashkenazi Jewishnot grpmax-eligible	0.00451%	22,154
South Asian	0.00313%	31,920
East Asian	0.00256%	39,068
European (non-Finnish)	0.00228%	43,765
Remaining individualsnot grpmax-eligible	0.00181%	55,196
African / African-American	0.00144%	69,262

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.Arg1647His
Coding: c.4940G>A
MANE Select: NM_182706
dbSNP: rs540090572
Type: single nucleotide variant
Location: chr8:143791191 (GRCh38)
Gene constraint: LOEUF 0.684 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 52.33 · 42 PDB

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-arg1647his (accessed [today's date]).

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