Is EGFR p.Ala859= (c.2577C>A) pathogenic?

EGFR p.Ala859= (c.2577C>A) is classified Benign/Likely benign in EGFR (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-03-28). Very rare (popmax 0.00133%, afr); Associated with EGFR-related lung cancer.

What condition is associated with EGFR p.Ala859= (c.2577C>A)?

EGFR p.Ala859= (c.2577C>A) is associated with EGFR-related lung cancer, lung cancer, hereditary neoplastic syndrome (ClinVar).

How common is EGFR p.Ala859= (c.2577C>A) in the general population?

EGFR p.Ala859= (c.2577C>A) is very rare (popmax 0.00133%, afr) (gnomAD).

EGFR p.Ala859=

c.2577C>A · rs1006848281 · VCV3015679

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

EGFR-related lung cancer

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 2.1	GERP -1.2, phastCons 1
Overall
CADD	12.96	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/74,922 alleles

Overall 0.000657% 1/152,142 alleles · very rare

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.Ala859=
Coding: c.2577C>A
MANE Select: NM_005228
dbSNP: rs1006848281
Type: single nucleotide variant
Location: chr7:55191826 (GRCh38)
Gene constraint: LOEUF 0.475 · pLI 0.98 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 76.29 · 393 PDB
Residue 859: a turn; the protein kinase domain

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

Disease context

Also linked: lung cancer hereditary neoplastic syndrome

Similar variants

EGFR p.Ala859Ser Uncertain significance ★ ⚠ same residue
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
EGFR c.1499-3C>T Uncertain significance ★★ same condition
EGFR c.1499-4G>T Uncertain significance ★★ same condition
EGFR c.1920-3C>T 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-ala859 (accessed [today's date]).

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