Is EGFR p.Arg671His (c.2012G>A) pathogenic?

EGFR p.Arg671His (c.2012G>A) is classified Uncertain significance in EGFR (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-04). AlphaMissense: likely benign (0.1149); Very rare (popmax 0.00102%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with EGFR p.Arg671His (c.2012G>A)?

EGFR p.Arg671His (c.2012G>A) is associated with hereditary neoplastic syndrome, lung cancer, inflammatory skin and bowel disease, neonatal, 2 (ClinVar).

How common is EGFR p.Arg671His (c.2012G>A) in the general population?

EGFR p.Arg671His (c.2012G>A) is very rare (popmax 0.00102%, nfe) (gnomAD).

What do computational predictors say about EGFR p.Arg671His (c.2012G>A)?

AlphaMissense predicts likely benign (score 0.1149) — an in-silico prediction, not a clinical call.

EGFR p.Arg671His

c.2012G>A · rs1266662784 · VCV943352

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1149 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00102%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1149	likely benign
REVEL	0.575	indeterminate
SaProt	LLR -8.69	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP 2.6, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 29 kb · p 1.1e-06 · regional, not allelic
Overall
CADD	29.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00102% European (non-Finnish) · 12/1,180,034 alleles

Filtering AF 0.000542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.000821% 12/1,460,930 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.Arg671His
Coding: c.2012G>A
MANE Select: NM_005228
dbSNP: rs1266662784
Type: single nucleotide variant
Location: chr7:55173075 (GRCh38)
Gene constraint: LOEUF 0.475 · pLI 0.98 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 76.29 · 393 PDB
Residue 671: a β-strand

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

Also linked: lung cancer inflammatory skin and bowel disease, neonatal, 2

Similar variants

EGFR p.Arg671Cys Uncertain significance ★★ ⚠ same residue
EGFR p.Arg671= Likely benign ★ same residue
EGFR p.Arg671Ser 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-arg671his (accessed [today's date]).

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