Is EGFR p.Ala722Val (c.2165C>T) pathogenic?

EGFR p.Ala722Val (c.2165C>T) is classified Conflicting classifications of pathogenicity in EGFR (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-10-29). AlphaMissense: likely pathogenic (0.9822); Very rare (popmax 0.000847%, nfe); Associated with lung cancer.

What condition is associated with EGFR p.Ala722Val (c.2165C>T)?

EGFR p.Ala722Val (c.2165C>T) is associated with lung cancer, hereditary neoplastic syndrome (ClinVar).

How common is EGFR p.Ala722Val (c.2165C>T) in the general population?

EGFR p.Ala722Val (c.2165C>T) is very rare (popmax 0.000847%, nfe) (gnomAD).

What do computational predictors say about EGFR p.Ala722Val (c.2165C>T)?

AlphaMissense predicts likely pathogenic (score 0.9822) — an in-silico prediction, not a clinical call.

EGFR p.Ala722Val

c.2165C>T · rs762494280 · VCV1903556

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9822 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000847%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

lung cancer

Computational evidence

Protein change
AlphaMissense	0.9822	likely pathogenic
REVEL	0.494	indeterminate
SaProt	LLR -10.96	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.84 · evaluated, not missing
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	24.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000847% European (non-Finnish) · 10/1,180,032 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.000684% 10/1,461,866 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.Ala722Val
Coding: c.2165C>T
MANE Select: NM_005228
dbSNP: rs762494280
Type: single nucleotide variant
Location: chr7:55174024 (GRCh38)
Gene constraint: LOEUF 0.475 · pLI 0.98 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 76.29 · 393 PDB
Residue 722: 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

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

Also linked: hereditary neoplastic syndrome

Similar variants

EGFR p.Ala722= Likely benign ★★ same residue
EGFR p.Ala722Ser 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

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-ala722val (accessed [today's date]).

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