Is EGFR p.Arg255Gln (c.764G>A) pathogenic?

EGFR p.Arg255Gln (c.764G>A) is classified Uncertain significance in EGFR (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-20). AlphaMissense: likely benign (0.0763); Ultra-rare (popmax 0.0493%, mid); Associated with EGFR-related lung cancer.

What condition is associated with EGFR p.Arg255Gln (c.764G>A)?

EGFR p.Arg255Gln (c.764G>A) is associated with EGFR-related lung cancer, hereditary neoplastic syndrome (ClinVar).

How common is EGFR p.Arg255Gln (c.764G>A) in the general population?

EGFR p.Arg255Gln (c.764G>A) is ultra-rare (popmax 0.0493%, mid) (gnomAD).

What do computational predictors say about EGFR p.Arg255Gln (c.764G>A)?

AlphaMissense predicts likely benign (score 0.0763) — an in-silico prediction, not a clinical call.

EGFR p.Arg255Gln

c.764G>A · rs372202099 · VCV862187

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0763 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0493%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

EGFR-related lung cancer

Computational evidence

Protein change
AlphaMissense	0.0763	likely benign
REVEL	0.159	moderately benign-leaning
SaProt	LLR -7.00	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 7.4	GERP 1.4, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 137 kb · p 6e-07 · regional, not allelic
Overall
CADD	21.5	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

Grpmax group 0.0493% Middle Eastern · 3/6,084 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00715%

Overall 0.00192% 31/1,614,042 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0493%	2,028
African / African-American	0.012%	8,323
South Asian	0.00439%	22,770
Remaining individualsnot grpmax-eligible	0.0016%	62,486
European (non-Finnish)	0.00119%	84,289

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.Arg255Gln
Coding: c.764G>A
MANE Select: NM_005228
dbSNP: rs372202099
Type: single nucleotide variant
Location: chr7:55154027 (GRCh38)
Gene constraint: LOEUF 0.475 · pLI 0.98 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 76.29 · 393 PDB
Residue 255: a β-strand; 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.Arg255Leu Uncertain significance ★ ⚠ same residue
EGFR p.Arg255Ter Conflicting classifications of pathogenicity ★ ⚠ same residue
EGFR p.Arg255Pro 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

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-arg255gln (accessed [today's date]).

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