Is EGF p.Leu1063= (c.3189A>G) pathogenic?

EGF p.Leu1063= (c.3189A>G) is classified Benign/Likely benign in EGF (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-10-27). Rare (popmax 0.369%, afr); Associated with renal hypomagnesemia 4.

What condition is associated with EGF p.Leu1063= (c.3189A>G)?

EGF p.Leu1063= (c.3189A>G) is associated with renal hypomagnesemia 4 (ClinVar).

How common is EGF p.Leu1063= (c.3189A>G) in the general population?

EGF p.Leu1063= (c.3189A>G) is rare (popmax 0.369%, afr) (gnomAD).

EGF p.Leu1063=

c.3189A>G · rs41456944 · VCV753723

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

rare (popmax 0.369%, afr)

Conditions

renal hypomagnesemia 4

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.2	GERP -3.1
Overall
CADD	0.951	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.369% African / African-American · 277/75,042 alleles

Filtering AF 0.333% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.319%

Overall 0.0209% 337/1,614,120 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.369%	271
Middle Eastern	0.165%	606
Remaining individualsnot grpmax-eligible	0.0368%	2,718
Admixed American	0.0267%	3,751
South Asian	0.0011%	91,082
European (non-Finnish)	0.000847%	117,999

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: EGF
Protein: p.Leu1063=
Coding: c.3189A>G
MANE Select: NM_001963
dbSNP: rs41456944
Type: single nucleotide variant
Location: chr4:110004520 (GRCh38)
Gene constraint: LOEUF 0.741 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.66 · 13 PDB

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

Disease context

renal hypomagnesemia 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EGF c.2221+4C>T Uncertain significance ★★ same condition
EGF c.2858-11G>T Uncertain significance ★★ same condition
EGF c.-60C>T Uncertain significance ★★ same condition
EGF p.Ala1025Ser Uncertain significance ★★ ⚠ same condition
EGF p.Ala1037Val Uncertain significance ★★ ⚠ same condition
EGF p.Arg213Gln Uncertain significance ★★ ⚠ same condition
EGF p.Arg221Thr Uncertain significance ★★ ⚠ same condition
EGF p.Arg351Gln Uncertain significance ★★ ⚠ same condition

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/egf-p-leu1063 (accessed [today's date]).

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