Is EGF p.Ala691= (c.2073A>G) pathogenic?

EGF p.Ala691= (c.2073A>G) is classified Benign in EGF (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-03). Common (popmax 23.6%, eas) — too common for a highly-penetrant pathogenic allele; Associated with renal hypomagnesemia 4.

What condition is associated with EGF p.Ala691= (c.2073A>G)?

EGF p.Ala691= (c.2073A>G) is associated with renal hypomagnesemia 4 (ClinVar).

EGF p.Ala691=

Q: How common is EGF p.Ala691= (c.2073A>G) in the general population?

EGF p.Ala691= (c.2073A>G) is common (popmax 23.6%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2073A>G · rs2302135 · VCV347242

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Common

common (popmax 23.6%, eas) — too common for a highly-penetrant pathogenic allele

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 -4.2	GERP -4.4
Overall
CADD	0.145	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 23.6% East Asian · 10,570/44,854 alleles

Filtering AF 23.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 23%

Overall 2.08% 33,571/1,613,934 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	23.6%	4
South Asian	13.1%	8
African / African-American	9.49%	11
Remaining individualsnot grpmax-eligible	2.87%	35
Ashkenazi Jewishnot grpmax-eligible	1.78%	56
Middle Eastern	1.55%	64
Admixed American	1.2%	83
European (non-Finnish)	0.0692%	1,444
Finnishnot grpmax-eligible	0.0437%	2,287

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.Ala691=
Coding: c.2073A>G
MANE Select: NM_001963
dbSNP: rs2302135
Type: single nucleotide variant
Location: chr4:109979991 (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 p.Ala691Thr Uncertain significance ★ ⚠ same residue
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

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-ala691 (accessed [today's date]).

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