Is EGF p.Val452Ile (c.1354G>A) pathogenic?

EGF p.Val452Ile (c.1354G>A) is classified Uncertain significance in EGF (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-12). AlphaMissense: likely benign (0.0632); Ultra-rare (popmax 0.076%, afr); Associated with renal hypomagnesemia 4.

What condition is associated with EGF p.Val452Ile (c.1354G>A)?

EGF p.Val452Ile (c.1354G>A) is associated with renal hypomagnesemia 4 (ClinVar).

How common is EGF p.Val452Ile (c.1354G>A) in the general population?

EGF p.Val452Ile (c.1354G>A) is ultra-rare (popmax 0.076%, afr) (gnomAD).

What do computational predictors say about EGF p.Val452Ile (c.1354G>A)?

AlphaMissense predicts likely benign (score 0.0632) — an in-silico prediction, not a clinical call.

EGF p.Val452Ile

c.1354G>A · rs142751045 · VCV1427951

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0632 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.076%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

renal hypomagnesemia 4

Computational evidence

Protein change
AlphaMissense	0.0632	likely benign
REVEL	0.274	benign-leaning
SaProt	LLR -5.82	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 -0.54	GERP -4.7
Regional constraint	o/e 0.90	unconstrained · MANE · 68 kb · p 0.00042 · regional, not allelic
Overall
CADD	0.269	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 0.076% African / African-American · 57/75,004 alleles

Filtering AF 0.0602% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0545%

Overall 0.00601% 97/1,613,988 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.076%	1,316
Ashkenazi Jewishnot grpmax-eligible	0.0237%	4,228
Remaining individualsnot grpmax-eligible	0.0144%	6,944
Admixed American	0.00667%	15,001
South Asian	0.00329%	30,363
East Asian	0.00223%	44,882
European (non-Finnish)	0.00136%	73,746

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.Val452Ile
Coding: c.1354G>A
MANE Select: NM_001963
dbSNP: rs142751045
Type: single nucleotide variant
Location: chr4:109963214 (GRCh38)
Gene constraint: LOEUF 0.741 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.66 · 13 PDB
Residue 452: the egf-like 4 domain; a disulfide bond

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-val452ile (accessed [today's date]).

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