Is ERBB2 p.His519Arg (c.1556A>G) pathogenic?

ERBB2 p.His519Arg (c.1556A>G) is classified Uncertain significance in ERBB2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-04-22). AlphaMissense: likely benign (0.087); Absent from gnomAD v4.1; Associated with ovarian cancer.

What condition is associated with ERBB2 p.His519Arg (c.1556A>G)?

ERBB2 p.His519Arg (c.1556A>G) is associated with ovarian cancer, gastric cancer, lung cancer (ClinVar).

How common is ERBB2 p.His519Arg (c.1556A>G) in the general population?

ERBB2 p.His519Arg (c.1556A>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ERBB2 p.His519Arg (c.1556A>G)?

AlphaMissense predicts likely benign (score 0.087) — an in-silico prediction, not a clinical call.

ERBB2 p.His519Arg

c.1556A>G · rs2145676083 · VCV2097466

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.087 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,607,024)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ovarian cancer

Computational evidence

Protein change
AlphaMissense	0.087	likely benign
REVEL	0.128	moderately benign-leaning
SaProt	LLR -4.55	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 6.2	GERP -0.29, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 16 kb · p 1.3e-16 · regional, not allelic
Overall
CADD	18.41	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

No allele count reported in gnomAD v4.1 (AN 1,607,024). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: ERBB2
Protein: p.His519Arg
Coding: c.1556A>G
MANE Select: NM_004448
dbSNP: rs2145676083
Type: single nucleotide variant
Location: chr17:39716343 (GRCh38)
Gene constraint: LOEUF 0.518 · pLI 0.06 (gnomAD)
Structure: AlphaFold pLDDT 74.65 · 63 PDB
Residue 519: a disulfide bond

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

Disease context

ovarian cancer — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: gastric cancer lung cancer glioma susceptibility 1 visceral neuropathy, familial, 2, autosomal recessive

Similar variants

ERBB2 p.Ala598Asp Uncertain significance ★★ ⚠ same condition
ERBB2 p.Arg1048Cys Uncertain significance ★★ ⚠ same condition
ERBB2 p.Arg188Cys Uncertain significance ★★ ⚠ same condition
ERBB2 p.Arg190Gln Uncertain significance ★★ ⚠ same condition
ERBB2 p.Arg203His Uncertain significance ★★ ⚠ same condition
ERBB2 p.Arg217Cys Uncertain significance ★★ ⚠ same condition
ERBB2 p.Arg517Gln Uncertain significance ★★ ⚠ same condition
ERBB2 p.Asp1084Tyr 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/erbb2-p-his519arg (accessed [today's date]).

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