Is EGFR p.Arg222Ser (c.664C>A) pathogenic?

EGFR p.Arg222Ser (c.664C>A) is classified Uncertain significance in EGFR (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-05-03). AlphaMissense: likely pathogenic (0.9902); Absent from gnomAD v4.1; Associated with EGFR-related lung cancer.

What condition is associated with EGFR p.Arg222Ser (c.664C>A)?

EGFR p.Arg222Ser (c.664C>A) is associated with EGFR-related lung cancer, hereditary neoplastic syndrome (ClinVar).

How common is EGFR p.Arg222Ser (c.664C>A) in the general population?

EGFR p.Arg222Ser (c.664C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about EGFR p.Arg222Ser (c.664C>A)?

AlphaMissense predicts likely pathogenic (score 0.9902) — an in-silico prediction, not a clinical call.

EGFR p.Arg222Ser

c.664C>A · rs1785212573 · VCV2189625

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9902 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

EGFR-related lung cancer

Computational evidence

Protein change
AlphaMissense	0.9902	likely pathogenic
REVEL	0.483	indeterminate
SaProt	LLR -12.06	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.8, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 137 kb · p 6e-07 · regional, not allelic
Overall
CADD	26.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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.Arg222Ser
Coding: c.664C>A
MANE Select: NM_005228
dbSNP: rs1785212573
Type: single nucleotide variant
Location: chr7:55152581 (GRCh38)
Gene constraint: LOEUF 0.475 · pLI 0.98 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 76.29 · 393 PDB
Residue 222: a disulfide bond; a UniProt-annotated variant site (variant egfr viii; found in a lung cancer sample; somatic mutation; induces lung cancer when exogenously expressed)

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.Arg222His Uncertain significance ★★ ⚠ same residue
EGFR p.Arg222Cys Uncertain significance ★ ⚠ same residue
EGFR p.Arg222Gly Uncertain significance ★ ⚠ same residue
EGFR p.Arg222Pro 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

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-arg222ser (accessed [today's date]).

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