Is ERBB2 p.Lys605= (c.1815A>G) pathogenic?

ERBB2 p.Lys605= (c.1815A>G) is classified Likely benign in ERBB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-09). Ultra-rare (popmax 0.0231%, sas).

How common is ERBB2 p.Lys605= (c.1815A>G) in the general population?

ERBB2 p.Lys605= (c.1815A>G) is ultra-rare (popmax 0.0231%, sas) (gnomAD).

ERBB2 p.Lys605=

c.1815A>G · rs538900246 · VCV2178032

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0231%, sas)

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 -0.17	GERP -5
Overall
CADD	4.682	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0231% South Asian · 21/91,012 alleles

Filtering AF 0.0154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0129%

Overall 0.00143% 23/1,612,900 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0231%	4,334
Remaining individualsnot grpmax-eligible	0.00321%	31,191

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: ERBB2
Protein: p.Lys605=
Coding: c.1815A>G
MANE Select: NM_004448
dbSNP: rs538900246
Type: single nucleotide variant
Location: chr17:39717397 (GRCh38)
Gene constraint: LOEUF 0.518 · pLI 0.06 (gnomAD)
Structure: AlphaFold pLDDT 74.65 · 63 PDB
Residue 605: a β-strand; a disulfide bond

Full ERBB2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ERBB2 p.Ala598Asp Uncertain significance ★★ ⚠ same type
ERBB2 p.Ala644Thr Uncertain significance ★★ ⚠ same type
ERBB2 p.Arg1048Cys Uncertain significance ★★ ⚠ same type
ERBB2 p.Arg188Cys Uncertain significance ★★ ⚠ same type
ERBB2 p.Arg188His Uncertain significance ★★ ⚠ same type
ERBB2 p.Arg190Gln Uncertain significance ★★ ⚠ same type
ERBB2 p.Arg203His Uncertain significance ★★ ⚠ same type
ERBB2 p.Arg217Cys Uncertain significance ★★ ⚠ same type

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/erbb2-p-lys605 (accessed [today's date]).

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