Is ERBB2 p.Thr216Met (c.647C>T) pathogenic?

ERBB2 p.Thr216Met (c.647C>T) is classified Uncertain significance in ERBB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-21). AlphaMissense: ambiguous (0.4721); Very rare (popmax 0.00501%, amr); Associated with ovarian cancer.

What condition is associated with ERBB2 p.Thr216Met (c.647C>T)?

ERBB2 p.Thr216Met (c.647C>T) is associated with ovarian cancer, gastric cancer, lung cancer (ClinVar).

How common is ERBB2 p.Thr216Met (c.647C>T) in the general population?

ERBB2 p.Thr216Met (c.647C>T) is very rare (popmax 0.00501%, amr) (gnomAD).

What do computational predictors say about ERBB2 p.Thr216Met (c.647C>T)?

AlphaMissense predicts ambiguous (score 0.4721) — an in-silico prediction, not a clinical call.

ERBB2 p.Thr216Met

c.647C>T · VCV3581926

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4721 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00501%, amr)

Conditions

ovarian cancer

Computational evidence

Protein change
AlphaMissense	0.4721	ambiguous
REVEL	0.634	indeterminate
SaProt	LLR -7.97	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.7, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 16 kb · p 1.3e-16 · regional, not allelic
Overall
CADD	28.6	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 0.00501% Admixed American · 3/59,936 alleles

Filtering AF 0.00154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0013%

Overall 0.00249% 40/1,605,858 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00501%	19,979
Remaining individualsnot grpmax-eligible	0.00482%	20,735
East Asian	0.00446%	22,409
African / African-American	0.00401%	24,961
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,544
European (non-Finnish)	0.00221%	45,290
Finnishnot grpmax-eligible	0.00168%	59,368
South Asian	0.0011%	90,916

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.Thr216Met
Coding: c.647C>T
MANE Select: NM_004448
Type: single nucleotide variant
Location: chr17:39710089 (GRCh38)
Gene constraint: LOEUF 0.518 · pLI 0.06 (gnomAD)
Structure: AlphaFold pLDDT 74.65 · 63 PDB

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.Thr216= Likely benign ★ same residue
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

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-thr216met (accessed [today's date]).

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