Is ERBB2 p.Glu1247fs (c.3738dup) pathogenic?

ERBB2 p.Glu1247fs (c.3738dup) is classified Uncertain significance in ERBB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-18). Very rare (popmax 0.00668%, amr).

How common is ERBB2 p.Glu1247fs (c.3738dup) in the general population?

ERBB2 p.Glu1247fs (c.3738dup) is very rare (popmax 0.00668%, amr) (gnomAD).

ERBB2 p.Glu1247fs

c.3738dup · rs752875197 · VCV2884781

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 0.00668%, amr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (27 of 27) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 4.9	GERP 0.003, phastCons 1
Overall
CADD	33.0	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 0.00668% Admixed American · 4/59,854 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.000373% 6/1,607,552 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00668%	14,963
European (non-Finnish)	0.00017%	589,175

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.Glu1247fs
Coding: c.3738dup
MANE Select: NM_004448
dbSNP: rs752875197
Type: Duplication
Location: chr17:39728013 (GRCh38)
Gene constraint: LOEUF 0.518 · pLI 0.06 (gnomAD)
Structure: AlphaFold pLDDT 74.65 · 63 PDB
Residue 1247: the 'disordered' region

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

Similar variants

ERBB2 p.Glu1247= Likely benign ★ same residue
ERBB2 p.Gly778_Pro780dup Pathogenic ★ same type
ERBB2 p.Tyr772_Ala775dup Likely pathogenic ★ same type
ERBB2 p.Ala1232fs Uncertain significance ★ same type
ERBB2 p.Gln984fs Uncertain significance ★ same type
ERBB2 c.1148+8_1148+11dup Likely benign ★ same type
ERBB2 c.1149-6dup Benign ★ same type
ERBB2 c.1737+12dup Likely benign ★ 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-glu1247fs (accessed [today's date]).

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