Is EGF p.Val562Leu (c.1684G>C) pathogenic?

EGF p.Val562Leu (c.1684G>C) is classified Uncertain significance in EGF (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-08-08). AlphaMissense: likely benign (0.2264); Ultra-rare (popmax 0.0534%, afr); Associated with renal hypomagnesemia 4.

What condition is associated with EGF p.Val562Leu (c.1684G>C)?

EGF p.Val562Leu (c.1684G>C) is associated with renal hypomagnesemia 4 (ClinVar).

How common is EGF p.Val562Leu (c.1684G>C) in the general population?

EGF p.Val562Leu (c.1684G>C) is ultra-rare (popmax 0.0534%, afr) (gnomAD).

What do computational predictors say about EGF p.Val562Leu (c.1684G>C)?

AlphaMissense predicts likely benign (score 0.2264) — an in-silico prediction, not a clinical call.

EGF p.Val562Leu

c.1684G>C · rs769513396 · VCV903650

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.2264 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0534%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

renal hypomagnesemia 4

Computational evidence

Protein change
AlphaMissense	0.2264	likely benign
REVEL	0.287	benign-leaning
SaProt	LLR -9.82	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.53	GERP -3.6
Regional constraint	o/e 0.90	unconstrained · MANE · 68 kb · p 0.00042 · regional, not allelic
Overall
CADD	9.528	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0534% African / African-American · 40/74,920 alleles

Filtering AF 0.0402% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0357%

Overall 0.00279% 45/1,614,046 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0534%	1,873
Remaining individualsnot grpmax-eligible	0.0064%	15,622
European (non-Finnish)	8.47e-05%	1,180,011

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.Val562Leu
Coding: c.1684G>C
MANE Select: NM_001963
dbSNP: rs769513396
Type: single nucleotide variant
Location: chr4:109969079 (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-val562leu (accessed [today's date]).

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