Is ERBB2 p.Lys615Arg (c.1844A>G) pathogenic?

ERBB2 p.Lys615Arg (c.1844A>G) is classified Uncertain significance in ERBB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-16). AlphaMissense: likely benign (0.2805); Very rare (popmax 0.00133%, afr).

How common is ERBB2 p.Lys615Arg (c.1844A>G) in the general population?

ERBB2 p.Lys615Arg (c.1844A>G) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about ERBB2 p.Lys615Arg (c.1844A>G)?

AlphaMissense predicts likely benign (score 0.2805) — an in-silico prediction, not a clinical call.

ERBB2 p.Lys615Arg

c.1844A>G · rs1312573525 · VCV1431605

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2805 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2805	likely benign
REVEL	0.449	indeterminate
SaProt	LLR -11.02	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.6, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 16 kb · p 1.3e-16 · regional, not allelic
Overall
CADD	26.3	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 0.00133% African / African-American · 1/75,024 alleles

Overall 0.000137% 2/1,461,102 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	75,024
South Asian	0.0011%	91,032

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.Lys615Arg
Coding: c.1844A>G
MANE Select: NM_004448
dbSNP: rs1312573525
Type: single nucleotide variant
Location: chr17:39717426 (GRCh38)
Gene constraint: LOEUF 0.518 · pLI 0.06 (gnomAD)
Structure: AlphaFold pLDDT 74.65 · 63 PDB
Residue 615: 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-lys615arg (accessed [today's date]).

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