Is EGFR p.Ala583= (c.1749C>T) pathogenic?

EGFR p.Ala583= (c.1749C>T) is classified Benign/Likely benign in EGFR (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-26). Rare (popmax 0.115%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with EGFR p.Ala583= (c.1749C>T)?

EGFR p.Ala583= (c.1749C>T) is associated with hereditary neoplastic syndrome (ClinVar).

How common is EGFR p.Ala583= (c.1749C>T) in the general population?

EGFR p.Ala583= (c.1749C>T) is rare (popmax 0.115%, afr) (gnomAD).

EGFR p.Ala583=

c.1749C>T · rs141232284 · VCV1168668

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

rare (popmax 0.115%, afr)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4.6	GERP -5.5
Overall
CADD	2.764	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.115% African / African-American · 86/75,024 alleles

Filtering AF 0.095% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0878%

Overall 0.00589% 95/1,614,152 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.115%	872
Remaining individualsnot grpmax-eligible	0.0064%	15,626
Admixed American	0.005%	20,009
South Asian	0.0022%	45,543

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.Ala583=
Coding: c.1749C>T
MANE Select: NM_005228
dbSNP: rs141232284
Type: single nucleotide variant
Location: chr7:55165306 (GRCh38)
Gene constraint: LOEUF 0.475 · pLI 0.98 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 76.29 · 393 PDB
Residue 583: a β-strand; a disulfide bond

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.Ala583Pro Uncertain significance ★ ⚠ same residue
EGFR p.Ala583Val 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-ala583 (accessed [today's date]).

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