Is EGFR p.Ala864= (c.2592G>A) pathogenic?

EGFR p.Ala864= (c.2592G>A) is classified Benign/Likely benign in EGFR (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-12-13). Ultra-rare (popmax 0.0351%, sas); Associated with lung cancer.

What condition is associated with EGFR p.Ala864= (c.2592G>A)?

EGFR p.Ala864= (c.2592G>A) is associated with lung cancer, hereditary neoplastic syndrome (ClinVar).

How common is EGFR p.Ala864= (c.2592G>A) in the general population?

EGFR p.Ala864= (c.2592G>A) is ultra-rare (popmax 0.0351%, sas) (gnomAD).

EGFR p.Ala864=

c.2592G>A · rs397517131 · VCV45288

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0351%, sas)

Conditions

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 -6.6	GERP -3.8
Overall
CADD	2.405	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0351% South Asian · 32/91,076 alleles

Filtering AF 0.0256% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0222%

Overall 0.00855% 138/1,613,968 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0351%	2,846
Middle Eastern	0.0165%	6,062
European (non-Finnish)	0.0083%	12,041
Remaining individualsnot grpmax-eligible	0.008%	12,502
East Asian	0.00223%	44,856
African / African-American	0.00133%	75,012

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.Ala864=
Coding: c.2592G>A
MANE Select: NM_005228
dbSNP: rs397517131
Type: single nucleotide variant
Location: chr7:55191841 (GRCh38)
Gene constraint: LOEUF 0.475 · pLI 0.98 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 76.29 · 393 PDB
Residue 864: a turn; the protein kinase domain

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: hereditary neoplastic syndrome

Similar variants

EGFR p.Ala864Thr Uncertain significance ★★ ⚠ same residue
EGFR p.Ala864Val 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

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-ala864 (accessed [today's date]).

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