Is EGFR p.Lys253Arg (c.758A>G) pathogenic?

EGFR p.Lys253Arg (c.758A>G) is classified Conflicting classifications of pathogenicity in EGFR (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-23). AlphaMissense: likely benign (0.0775); Ultra-rare (popmax 0.0267%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with EGFR p.Lys253Arg (c.758A>G)?

EGFR p.Lys253Arg (c.758A>G) is associated with hereditary neoplastic syndrome (ClinVar).

How common is EGFR p.Lys253Arg (c.758A>G) in the general population?

EGFR p.Lys253Arg (c.758A>G) is ultra-rare (popmax 0.0267%, eas) (gnomAD).

What do computational predictors say about EGFR p.Lys253Arg (c.758A>G)?

AlphaMissense predicts likely benign (score 0.0775) — an in-silico prediction, not a clinical call.

EGFR p.Lys253Arg

c.758A>G · rs374084791 · VCV936935

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0775 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0267%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0775	likely benign
REVEL	0.182	moderately benign-leaning
SaProt	LLR -7.19	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 -0.52	GERP -4.7
Regional constraint	o/e 0.75	unconstrained · MANE · 137 kb · p 6e-07 · regional, not allelic
Overall
CADD	4.741	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 0.0267% East Asian · 12/44,870 alleles

Filtering AF 0.0154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0121%

Overall 0.00316% 51/1,614,120 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0267%	3,739
Remaining individualsnot grpmax-eligible	0.0224%	4,465
South Asian	0.0187%	5,357
African / African-American	0.00666%	15,004
Admixed American	0.005%	20,008

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.Lys253Arg
Coding: c.758A>G
MANE Select: NM_005228
dbSNP: rs374084791
Type: single nucleotide variant
Location: chr7:55154021 (GRCh38)
Gene constraint: LOEUF 0.475 · pLI 0.98 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 76.29 · 393 PDB
Residue 253: a β-strand; a disulfide bond; a UniProt-annotated variant site (variant egfr viii; found in a lung cancer sample; somatic mutation; induces lung cancer when exogenously expressed)

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 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
EGFR c.2061+3G>A 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-lys253arg (accessed [today's date]).

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