Is SCRIB p.Glu480Lys (c.1438G>A) pathogenic?

SCRIB p.Glu480Lys (c.1438G>A) is classified Uncertain significance in SCRIB (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-19). AlphaMissense: likely pathogenic (0.8476); Ultra-rare (popmax 0.0111%, nfe).

How common is SCRIB p.Glu480Lys (c.1438G>A) in the general population?

SCRIB p.Glu480Lys (c.1438G>A) is ultra-rare (popmax 0.0111%, nfe) (gnomAD).

What do computational predictors say about SCRIB p.Glu480Lys (c.1438G>A)?

AlphaMissense predicts likely pathogenic (score 0.8476) — an in-silico prediction, not a clinical call.

SCRIB p.Glu480Lys

c.1438G>A · VCV4581364

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8476 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0111%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.8476	likely pathogenic
REVEL	0.508	indeterminate
SaProt	LLR -5.88	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.7, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 20 kb · p 9.1e-08 · regional, not allelic
Overall
CADD	29.1	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 0.0111% European (non-Finnish) · 131/1,179,994 alleles

Filtering AF 0.00953% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00896%

Overall 0.00861% 139/1,613,560 alleles · ultra-rare exomes 129/1,461,374 · genomes 10/152,186 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0111%	9,008
Remaining individualsnot grpmax-eligible	0.0064%	15,620
African / African-American	0.004%	24,973
Admixed American	0.00167%	60,006

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.Glu480Lys
Coding: c.1438G>A
MANE Select: NM_182706
Type: single nucleotide variant
Location: chr8:143810571 (GRCh38)
Gene constraint: LOEUF 0.684 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 52.33 · 42 PDB
Residue 480: the 'sufficient for targeting to adherens junction and to inhibit cell proliferation' region; the 'disordered' region

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

Similar variants

SCRIB p.Glu480Gly 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-glu480lys (accessed [today's date]).

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