Is EGFR p.Leu703= (c.2109C>G) pathogenic?

EGFR p.Leu703= (c.2109C>G) is classified Likely benign in EGFR (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-22). Very rare (popmax 0.00329%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with EGFR p.Leu703= (c.2109C>G)?

EGFR p.Leu703= (c.2109C>G) is associated with hereditary neoplastic syndrome (ClinVar).

How common is EGFR p.Leu703= (c.2109C>G) in the general population?

EGFR p.Leu703= (c.2109C>G) is very rare (popmax 0.00329%, sas) (gnomAD).

EGFR p.Leu703=

c.2109C>G · rs746027140 · VCV1537251

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Conditions

hereditary neoplastic syndrome

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 -0.95	GERP -5.3
Overall
CADD	1.709	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00329% South Asian · 3/91,084 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000205% 3/1,461,890 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.Leu703=
Coding: c.2109C>G
MANE Select: NM_005228
dbSNP: rs746027140
Type: single nucleotide variant
Location: chr7:55173968 (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

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EGFR p.Leu703Ile Uncertain significance ★★ ⚠ same residue
EGFR p.Leu703Phe 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-leu703 (accessed [today's date]).

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