Is EGFR p.Ile878= (c.2634C>T) pathogenic?

EGFR p.Ile878= (c.2634C>T) is classified Conflicting classifications of pathogenicity in EGFR (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-04-28). Ultra-rare (popmax 0.0143%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with EGFR p.Ile878= (c.2634C>T)?

EGFR p.Ile878= (c.2634C>T) is associated with hereditary neoplastic syndrome (ClinVar).

How common is EGFR p.Ile878= (c.2634C>T) in the general population?

EGFR p.Ile878= (c.2634C>T) is ultra-rare (popmax 0.0143%, sas) (gnomAD).

EGFR p.Ile878=

c.2634C>T · rs757939047 · VCV1989301

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0143%, sas)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.27	acceptor loss, 8 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 1.1	GERP -0.41, phastCons 1
Overall
CADD	6.936	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0143% South Asian · 13/91,088 alleles

Filtering AF 0.00844% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00661%

Overall 0.000867% 14/1,614,036 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0143%	7,007
Remaining individualsnot grpmax-eligible	0.0016%	62,488

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.Ile878=
Coding: c.2634C>T
MANE Select: NM_005228
dbSNP: rs757939047
Type: single nucleotide variant
Location: chr7:55192774 (GRCh38)
Gene constraint: LOEUF 0.475 · pLI 0.98 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 76.29 · 393 PDB
Residue 878: an α-helix; the protein kinase domain

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

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EGFR p.Ile878Val 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
EGFR c.1920-3C>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-ile878 (accessed [today's date]).

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