Is EGFR p.Gln684Arg (c.2051A>G) pathogenic?

EGFR p.Gln684Arg (c.2051A>G) is classified Uncertain significance in EGFR (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-18). AlphaMissense: ambiguous (0.3832); Very rare (popmax 8.47e-05%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with EGFR p.Gln684Arg (c.2051A>G)?

EGFR p.Gln684Arg (c.2051A>G) is associated with hereditary neoplastic syndrome (ClinVar).

How common is EGFR p.Gln684Arg (c.2051A>G) in the general population?

EGFR p.Gln684Arg (c.2051A>G) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about EGFR p.Gln684Arg (c.2051A>G)?

AlphaMissense predicts ambiguous (score 0.3832) — an in-silico prediction, not a clinical call.

EGFR p.Gln684Arg

c.2051A>G · rs1427460008 · VCV2795097

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3832 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.3832	ambiguous
REVEL	0.394	indeterminate
SaProt	LLR -7.18	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.3	GERP 2.6, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 29 kb · p 1.1e-06 · regional, not allelic
Overall
CADD	26.5	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 8.47e-05% European (non-Finnish) · 1/1,179,948 alleles

Overall 6.86e-05% 1/1,458,248 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.Gln684Arg
Coding: c.2051A>G
MANE Select: NM_005228
dbSNP: rs1427460008
Type: single nucleotide variant
Location: chr7:55173114 (GRCh38)
Gene constraint: LOEUF 0.475 · pLI 0.98 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 76.29 · 393 PDB
Residue 684: an α-helix

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.Gln684Glu 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-gln684arg (accessed [today's date]).

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