Is EGFR p.Arg255Pro (c.764G>C) pathogenic?

EGFR p.Arg255Pro (c.764G>C) is classified Uncertain significance in EGFR (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-23). AlphaMissense: likely pathogenic (0.9402); Absent from gnomAD v4.1.

How common is EGFR p.Arg255Pro (c.764G>C) in the general population?

EGFR p.Arg255Pro (c.764G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about EGFR p.Arg255Pro (c.764G>C)?

AlphaMissense predicts likely pathogenic (score 0.9402) — an in-silico prediction, not a clinical call.

EGFR p.Arg255Pro

c.764G>C · VCV4896084

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9402 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9402	likely pathogenic
REVEL	0.446	indeterminate
SaProt	LLR -14.73	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 7.4	GERP 1.4, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 137 kb · p 6e-07 · regional, not allelic
Overall
CADD	28.5	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.Arg255Pro
Coding: c.764G>C
MANE Select: NM_005228
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

Similar variants

EGFR p.Arg255Gln Uncertain significance ★★ ⚠ same residue
EGFR p.Arg255Leu Uncertain significance ★ ⚠ same residue
EGFR p.Arg255Ter Conflicting classifications of pathogenicity ★ ⚠ same residue
EGFR p.Gly428Asp Pathogenic ★★ same type
EGFR c.1207+5G>A Uncertain significance ★★ same type
EGFR c.1298+3A>G Uncertain significance ★★ same type
EGFR c.1298+4A>G Uncertain significance ★★ same type
EGFR c.1298+6T>C Uncertain significance ★★ same type

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-arg255pro (accessed [today's date]).

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