Is EGFR p.Pro3Leu (c.8C>T) pathogenic?

EGFR p.Pro3Leu (c.8C>T) is classified Conflicting classifications of pathogenicity in EGFR (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-08-28). AlphaMissense: likely benign (0.1713); Very rare (popmax 0.000267%, nfe); Associated with lung cancer.

What condition is associated with EGFR p.Pro3Leu (c.8C>T)?

EGFR p.Pro3Leu (c.8C>T) is associated with lung cancer, inflammatory skin and bowel disease, neonatal, 2, hereditary neoplastic syndrome (ClinVar).

How common is EGFR p.Pro3Leu (c.8C>T) in the general population?

EGFR p.Pro3Leu (c.8C>T) is very rare (popmax 0.000267%, nfe) (gnomAD).

What do computational predictors say about EGFR p.Pro3Leu (c.8C>T)?

AlphaMissense predicts likely benign (score 0.1713) — an in-silico prediction, not a clinical call.

EGFR p.Pro3Leu

c.8C>T · rs749433287 · VCV1017706

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1713 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000267%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

lung cancer

Computational evidence

Protein change
AlphaMissense	0.1713	likely benign
REVEL	0.175	moderately benign-leaning
SaProt	LLR -6.11	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.28	GERP 0.3, phastCons 0.009
Regional constraint	o/e 1.72	unconstrained · MANE · 84 bp · p 9.2e-06 · regional, not allelic
Overall
CADD	17.42	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 0.000267% European (non-Finnish) · 3/1,121,754 alleles

Filtering AF 7.1e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 2e-05%

Overall 0.000222% 3/1,353,762 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.Pro3Leu
Coding: c.8C>T
MANE Select: NM_005228
dbSNP: rs749433287
Type: single nucleotide variant
Location: chr7:55019285 (GRCh38)
Gene constraint: LOEUF 0.475 · pLI 0.98 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 76.29 · 393 PDB

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: inflammatory skin and bowel disease, neonatal, 2 hereditary neoplastic syndrome

Similar variants

EGFR p.Pro3= Likely benign ★★ same residue
EGFR p.Pro3Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
EGFR p.Pro3Ala Uncertain significance ★ ⚠ same residue
EGFR p.Gly428Asp Pathogenic ★★ same condition
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

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-pro3leu (accessed [today's date]).

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