Is EGFR p.Glu519Asp (c.1557G>T) pathogenic?

EGFR p.Glu519Asp (c.1557G>T) is classified Conflicting classifications of pathogenicity in EGFR (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-19). AlphaMissense: likely benign (0.0748); Ultra-rare (popmax 0.0799%, afr); Associated with lung cancer.

What condition is associated with EGFR p.Glu519Asp (c.1557G>T)?

EGFR p.Glu519Asp (c.1557G>T) is associated with lung cancer, inflammatory skin and bowel disease, neonatal, 2, hereditary neoplastic syndrome (ClinVar).

How common is EGFR p.Glu519Asp (c.1557G>T) in the general population?

EGFR p.Glu519Asp (c.1557G>T) is ultra-rare (popmax 0.0799%, afr) (gnomAD).

What do computational predictors say about EGFR p.Glu519Asp (c.1557G>T)?

AlphaMissense predicts likely benign (score 0.0748) — an in-silico prediction, not a clinical call.

EGFR p.Glu519Asp

c.1557G>T · rs116057045 · VCV857836

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0748 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0799%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

lung cancer

Computational evidence

Protein change
AlphaMissense	0.0748	likely benign
REVEL	0.033	moderately benign-leaning
SaProt	LLR -5.68	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 -1.7	GERP -4.5
Regional constraint	o/e 0.85	unconstrained · MANE · 8,628 bp · p 0.0087 · regional, not allelic
Overall
CADD	1.231	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 0.0799% African / African-American · 60/75,076 alleles

Filtering AF 0.0637% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0578%

Overall 0.0039% 63/1,614,276 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0799%	1,251
Remaining individualsnot grpmax-eligible	0.0032%	31,255
Admixed American	0.00167%	60,038

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: EGFR
Protein: p.Glu519Asp
Coding: c.1557G>T
MANE Select: NM_005228
dbSNP: rs116057045
Type: single nucleotide variant
Location: chr7:55161557 (GRCh38)
Gene constraint: LOEUF 0.475 · pLI 0.98 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 76.29 · 393 PDB
Residue 519: a β-strand; a disulfide bond

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

Disease context

lung cancer — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: inflammatory skin and bowel disease, neonatal, 2 hereditary neoplastic syndrome

Similar variants

EGFR p.Glu519Gly Uncertain significance ★★ ⚠ same residue
EGFR p.Glu519Gln Uncertain significance ★ same residue
EGFR p.Glu519= Likely benign ★ same residue
EGFR p.Gly428Asp Pathogenic ★★ same condition
EGFR c.1207+5G>A Uncertain significance ★★ same condition
EGFR c.1298+3A>G Uncertain significance ★★ same condition
EGFR c.1298+4A>G Uncertain significance ★★ same condition
EGFR c.1298+6T>C 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/egfr-p-glu519asp (accessed [today's date]).

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