Is EGFR p.Ile646Phe (c.1936A>T) pathogenic?

EGFR p.Ile646Phe (c.1936A>T) is classified Likely pathogenic in EGFR (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-01). AlphaMissense: likely benign (0.2042); Absent from gnomAD v4.1; Associated with ovarian cancer.

What condition is associated with EGFR p.Ile646Phe (c.1936A>T)?

EGFR p.Ile646Phe (c.1936A>T) is associated with ovarian cancer (ClinVar).

How common is EGFR p.Ile646Phe (c.1936A>T) in the general population?

EGFR p.Ile646Phe (c.1936A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about EGFR p.Ile646Phe (c.1936A>T)?

AlphaMissense predicts likely benign (score 0.2042) — an in-silico prediction, not a clinical call.

EGFR p.Ile646Phe

c.1936A>T · rs140516819 · VCV2445337

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2042 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ovarian cancer

Computational evidence

Protein change
AlphaMissense	0.2042	likely benign ⚠ discordant with ClinVar
REVEL	0.684	pathogenic-leaning
SaProt	LLR -9.01	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP 2.6, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 29 kb · p 1.1e-06 · regional, not allelic
Overall
CADD	23.8	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

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.Ile646Phe
Coding: c.1936A>T
MANE Select: NM_005228
dbSNP: rs140516819
Type: single nucleotide variant
Location: chr7:55172999 (GRCh38)
Gene constraint: LOEUF 0.475 · pLI 0.98 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 76.29 · 393 PDB
Residue 646: a β-strand

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

Disease context

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

Similar variants

EGFR p.Ile646Ser Uncertain significance ★★ ⚠ same residue
EGFR p.Ile646Val Uncertain significance ★★ ⚠ same residue
EGFR p.Ile646= Likely benign ★★ same residue
EGFR p.Ile646Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
EGFR p.Ile646Thr Uncertain significance ★ same residue
EGFR p.Val592Ile Benign/Likely benign ★★ ⚠ same condition
EGFR p.Ala21Thr Conflicting classifications of pathogenicity ★ ⚠ same condition
EGFR p.Arg836Cys Conflicting classifications of pathogenicity ★ ⚠ 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-ile646phe (accessed [today's date]).

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