Is SCRIB p.Glu1489Lys (c.4465G>A) pathogenic?

SCRIB p.Glu1489Lys (c.4465G>A) is classified Uncertain significance in SCRIB (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-17). AlphaMissense: likely pathogenic (0.8655); Very rare (popmax 0.00404%, afr).

How common is SCRIB p.Glu1489Lys (c.4465G>A) in the general population?

SCRIB p.Glu1489Lys (c.4465G>A) is very rare (popmax 0.00404%, afr) (gnomAD).

What do computational predictors say about SCRIB p.Glu1489Lys (c.4465G>A)?

AlphaMissense predicts likely pathogenic (score 0.8655) — an in-silico prediction, not a clinical call.

SCRIB p.Glu1489Lys

c.4465G>A · rs1479572942 · VCV2526255

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8655 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00404%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8655	likely pathogenic
REVEL	0.258	benign-leaning
SaProt	LLR -9.91	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 5.7	GERP 1.4, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 20 kb · p 9.1e-08 · regional, not allelic
Overall
CADD	25.1	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 0.00404% African / African-American · 3/74,168 alleles

Filtering AF 0.00107% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000498%

Overall 0.000509% 8/1,570,686 alleles · very rare exomes 5/1,418,496 · genomes 3/152,190 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00404%	24,723
European (non-Finnish)	0.000429%	233,153

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.Glu1489Lys
Coding: c.4465G>A
MANE Select: NM_182706
dbSNP: rs1479572942
Type: single nucleotide variant
Location: chr8:143792269 (GRCh38)
Gene constraint: LOEUF 0.684 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 52.33 · 42 PDB
Residue 1489: 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-glu1489lys (accessed [today's date]).

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