Is ERBB2 p.Ala847= (c.2541C>T) pathogenic?

ERBB2 p.Ala847= (c.2541C>T) is classified Likely benign in ERBB2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-12). Ultra-rare (popmax 0.075%, amr).

How common is ERBB2 p.Ala847= (c.2541C>T) in the general population?

ERBB2 p.Ala847= (c.2541C>T) is ultra-rare (popmax 0.075%, amr) (gnomAD).

ERBB2 p.Ala847=

c.2541C>T · rs140231769 · VCV1156898

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.075%, amr)

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 -1.4	GERP -5.1, phastCons 0.001
Overall
CADD	15.33	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.075% Admixed American · 45/60,018 alleles

Filtering AF 0.0575% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0523%

Overall 0.0476% 768/1,614,108 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.075%	1,334
European (non-Finnish)	0.0574%	1,743
Remaining individualsnot grpmax-eligible	0.0384%	2,605
Middle Eastern	0.0165%	6,062
South Asian	0.0154%	6,506
African / African-American	0.00933%	10,713

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.Ala847=
Coding: c.2541C>T
MANE Select: NM_004448
dbSNP: rs140231769
Type: single nucleotide variant
Location: chr17:39725096 (GRCh38)
Gene constraint: LOEUF 0.518 · pLI 0.06 (gnomAD)
Structure: AlphaFold pLDDT 74.65 · 63 PDB
Residue 847: the protein kinase domain

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-ala847 (accessed [today's date]).

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