Is ERBB2 p.Ile946fs (c.2835_2836insT) pathogenic?

ERBB2 p.Ile946fs (c.28352836insT) is classified Uncertain significance in ERBB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-08). Very rare (popmax 0.00935%, afr); Associated with ovarian cancer.

What condition is associated with ERBB2 p.Ile946fs (c.2835_2836insT)?

ERBB2 p.Ile946fs (c.2835_2836insT) is associated with ovarian cancer, gastric cancer, lung cancer (ClinVar).

How common is ERBB2 p.Ile946fs (c.2835_2836insT) in the general population?

ERBB2 p.Ile946fs (c.2835_2836insT) is very rare (popmax 0.00935%, afr) (gnomAD).

ERBB2 p.Ile946fs

c.2835_2836insT · VCV3581938

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00935%, afr)

Conditions

ovarian cancer

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 23 of 27
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -5.3	GERP -5.4
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00935% African / African-American · 7/74,896 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00309%

Overall 0.000434% 7/1,613,804 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: ERBB2
Protein: p.Ile946fs
Coding: c.2835_2836insT
MANE Select: NM_004448
Type: Insertion
Location: chr17:39725816 (GRCh38)
Gene constraint: LOEUF 0.518 · pLI 0.06 (gnomAD)
Structure: AlphaFold pLDDT 74.65 · 63 PDB
Residue 946: the protein kinase domain

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-ile946fs (accessed [today's date]).

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