Is EGFR p.Phe549= (c.1647T>C) pathogenic?

EGFR p.Phe549= (c.1647T>C) is classified Likely benign in EGFR (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-16). Very rare (popmax 0.00329%, sas); Associated with EGFR-related lung cancer.

What condition is associated with EGFR p.Phe549= (c.1647T>C)?

EGFR p.Phe549= (c.1647T>C) is associated with EGFR-related lung cancer (ClinVar).

How common is EGFR p.Phe549= (c.1647T>C) in the general population?

EGFR p.Phe549= (c.1647T>C) is very rare (popmax 0.00329%, sas) (gnomAD).

EGFR p.Phe549=

c.1647T>C · VCV3677115

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Conditions

EGFR-related 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 -2.5	GERP -4
Overall
CADD	5.537	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00329% South Asian · 3/91,090 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000186% 3/1,614,250 alleles · very rare exomes 3/1,461,886 · genomes 0/152,364 · joint denominator

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.Phe549=
Coding: c.1647T>C
MANE Select: NM_005228
Type: single nucleotide variant
Location: chr7:55163748 (GRCh38)
Gene constraint: LOEUF 0.475 · pLI 0.98 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 76.29 · 393 PDB
Residue 549: a β-strand

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

Disease context

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

Similar variants

EGFR p.Phe549Ser Uncertain significance ★★ ⚠ same residue
EGFR c.1499-3C>T Uncertain significance ★★ same condition
EGFR c.2061+5G>A Uncertain significance ★★ same condition
EGFR c.2061+5G>T Uncertain significance ★★ same condition
EGFR c.2062-3C>G Uncertain significance ★★ same condition
EGFR c.3114+4T>G Uncertain significance ★★ same condition
EGFR c.3271+3G>A Uncertain significance ★★ same condition
EGFR c.629-3C>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-phe549 (accessed [today's date]).

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