Is EGFR p.Pro741= (c.2223C>T) pathogenic?

EGFR p.Pro741= (c.2223C>T) is classified Benign/Likely benign in EGFR (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-04). Ultra-rare (popmax 0.0283%, amr); Associated with lung cancer.

What condition is associated with EGFR p.Pro741= (c.2223C>T)?

EGFR p.Pro741= (c.2223C>T) is associated with lung cancer, hereditary neoplastic syndrome (ClinVar).

How common is EGFR p.Pro741= (c.2223C>T) in the general population?

EGFR p.Pro741= (c.2223C>T) is ultra-rare (popmax 0.0283%, amr) (gnomAD).

EGFR p.Pro741=

c.2223C>T · rs372772241 · VCV1100680

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0283%, amr)

Conditions

lung cancer

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 -9.3	GERP -5.3
Overall
CADD	6.396	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0283% Admixed American · 17/60,002 alleles

Filtering AF 0.018% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0147%

Overall 0.00409% 66/1,613,848 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0283%	3,530
East Asian	0.02%	4,988
African / African-American	0.0134%	7,491
European (non-Finnish)	0.00246%	40,687
Remaining individualsnot grpmax-eligible	0.0016%	62,472

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.Pro741=
Coding: c.2223C>T
MANE Select: NM_005228
dbSNP: rs372772241
Type: single nucleotide variant
Location: chr7:55174760 (GRCh38)
Gene constraint: LOEUF 0.475 · pLI 0.98 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 76.29 · 393 PDB
Residue 741: a β-strand; the protein kinase domain

Full EGFR gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

lung cancer — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary neoplastic syndrome

Similar variants

EGFR p.Pro741Leu 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-pro741 (accessed [today's date]).

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