Is EGFR p.Ser720Phe (c.2159C>T) pathogenic?

EGFR p.Ser720Phe (c.2159C>T) is classified Uncertain significance in EGFR (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-08). AlphaMissense: likely pathogenic (0.6587); Very rare (popmax 8.47e-05%, nfe); Associated with EGFR-related lung cancer.

What condition is associated with EGFR p.Ser720Phe (c.2159C>T)?

EGFR p.Ser720Phe (c.2159C>T) is associated with EGFR-related lung cancer (ClinVar).

How common is EGFR p.Ser720Phe (c.2159C>T) in the general population?

EGFR p.Ser720Phe (c.2159C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about EGFR p.Ser720Phe (c.2159C>T)?

AlphaMissense predicts likely pathogenic (score 0.6587) — an in-silico prediction, not a clinical call.

EGFR p.Ser720Phe

c.2159C>T · rs772799315 · VCV2802797

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6587 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

EGFR-related lung cancer

Computational evidence

Protein change
AlphaMissense	0.6587	likely pathogenic
REVEL	0.605	indeterminate
SaProt	LLR -11.27	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 7.6	GERP 2.5, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 29 kb · p 1.1e-06 · regional, not allelic
Overall
CADD	25.5	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

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,048 alleles

Overall 6.84e-05% 1/1,461,878 alleles · very rare

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.Ser720Phe
Coding: c.2159C>T
MANE Select: NM_005228
dbSNP: rs772799315
Type: single nucleotide variant
Location: chr7:55174018 (GRCh38)
Gene constraint: LOEUF 0.475 · pLI 0.98 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 76.29 · 393 PDB
Residue 720: a binding site; a β-strand; the protein kinase domain

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.Ser720Cys Uncertain significance ★ ⚠ same residue
EGFR p.Ser720= Benign/Likely benign ★★ 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

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-ser720phe (accessed [today's date]).

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