Is EGFR p.Pro596Ser (c.1786C>T) pathogenic?

EGFR p.Pro596Ser (c.1786C>T) is classified Pathogenic in EGFR (ClinVar, No assertion criteria, 1 submitter). AlphaMissense: likely pathogenic (0.796); Absent from gnomAD v4.1; Associated with urinary bladder cancer.

What condition is associated with EGFR p.Pro596Ser (c.1786C>T)?

EGFR p.Pro596Ser (c.1786C>T) is associated with urinary bladder cancer (ClinVar).

How common is EGFR p.Pro596Ser (c.1786C>T) in the general population?

EGFR p.Pro596Ser (c.1786C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about EGFR p.Pro596Ser (c.1786C>T)?

AlphaMissense predicts likely pathogenic (score 0.796) — an in-silico prediction, not a clinical call.

EGFR p.Pro596Ser

c.1786C>T · rs2128946276 · VCV2582280

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.796 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

urinary bladder cancer

Computational evidence

Protein change
AlphaMissense	0.796	likely pathogenic ✓ concordant with ClinVar
REVEL	0.495	indeterminate
SaProt	LLR -9.71	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.7, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 8,628 bp · p 0.0087 · regional, not allelic
Overall
CADD	26.0	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.Pro596Ser
Coding: c.1786C>T
MANE Select: NM_005228
dbSNP: rs2128946276
Type: single nucleotide variant
Location: chr7:55165343 (GRCh38)
Gene constraint: LOEUF 0.475 · pLI 0.98 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 76.29 · 393 PDB
Residue 596: a disulfide bond

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

Disease context

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

Similar variants

EGFR p.Pro596Leu Uncertain significance ★★ ⚠ same residue
EGFR p.Pro596= Likely benign ★★ same residue
EGFR p.Pro596Gln Uncertain significance ★ ⚠ same residue
EGFR p.Gly863Ser Uncertain significance ★★ ⚠ same condition
EGFR p.Ala763Thr Pathogenic same condition
EGFR p.Gly598Arg Pathogenic same condition
EGFR p.Thr854Ile Pathogenic same condition
EGFR p.Gly428Asp Pathogenic ★★ same type

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-pro596ser (accessed [today's date]).

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