Is EGFR p.Leu703Ile (c.2107C>A) pathogenic?

EGFR p.Leu703Ile (c.2107C>A) is classified Uncertain significance in EGFR (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-13). AlphaMissense: likely benign (0.2618); Absent from gnomAD v4.1; Associated with EGFR-related lung cancer.

What condition is associated with EGFR p.Leu703Ile (c.2107C>A)?

EGFR p.Leu703Ile (c.2107C>A) is associated with EGFR-related lung cancer, hereditary neoplastic syndrome (ClinVar).

How common is EGFR p.Leu703Ile (c.2107C>A) in the general population?

EGFR p.Leu703Ile (c.2107C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about EGFR p.Leu703Ile (c.2107C>A)?

AlphaMissense predicts likely benign (score 0.2618) — an in-silico prediction, not a clinical call.

EGFR p.Leu703Ile

c.2107C>A · rs1273890779 · VCV2002168

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2618 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

EGFR-related lung cancer

Computational evidence

Protein change
AlphaMissense	0.2618	likely benign
REVEL	0.263	benign-leaning
SaProt	LLR -8.47	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 7.6	GERP 2.6, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 29 kb · p 1.1e-06 · regional, not allelic
Overall
CADD	24.3	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: EGFR
Protein: p.Leu703Ile
Coding: c.2107C>A
MANE Select: NM_005228
dbSNP: rs1273890779
Type: single nucleotide variant
Location: chr7:55173966 (GRCh38)
Gene constraint: LOEUF 0.475 · pLI 0.98 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 76.29 · 393 PDB
Residue 703: a β-strand; the 'important for dimerization, phosphorylation and activation' region

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

Disease context

Also linked: hereditary neoplastic syndrome

Similar variants

EGFR p.Leu703Phe Uncertain significance ★★ ⚠ same residue
EGFR p.Leu703= Likely benign ★★ 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-leu703ile (accessed [today's date]).

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