Is ERBB2 p.Pro1037Leu (c.3110C>T) pathogenic?

ERBB2 p.Pro1037Leu (c.3110C>T) is classified Uncertain significance in ERBB2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-02-23). AlphaMissense: likely benign (0.0699); Ultra-rare (popmax 0.0535%, amr); Associated with ovarian cancer.

What condition is associated with ERBB2 p.Pro1037Leu (c.3110C>T)?

ERBB2 p.Pro1037Leu (c.3110C>T) is associated with ovarian cancer, gastric cancer, lung cancer (ClinVar).

How common is ERBB2 p.Pro1037Leu (c.3110C>T) in the general population?

ERBB2 p.Pro1037Leu (c.3110C>T) is ultra-rare (popmax 0.0535%, amr) (gnomAD).

What do computational predictors say about ERBB2 p.Pro1037Leu (c.3110C>T)?

AlphaMissense predicts likely benign (score 0.0699) — an in-silico prediction, not a clinical call.

ERBB2 p.Pro1037Leu

c.3110C>T · rs201905649 · VCV2074936

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0699 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0535%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ovarian cancer

Computational evidence

Protein change
AlphaMissense	0.0699	likely benign
REVEL	0.07	moderately benign-leaning
SaProt	LLR -6.85	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 0.51	GERP -0.99, phastCons 0.001
Regional constraint	o/e 0.91	unconstrained · MANE · 1,215 bp · p 0.086 · regional, not allelic
Overall
CADD	10.64	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

Grpmax group 0.0535% Admixed American · 32/59,844 alleles

Filtering AF 0.0389% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.034%

Overall 0.00459% 74/1,612,154 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0535%	1,870
East Asian	0.0267%	3,740
Remaining individualsnot grpmax-eligible	0.0176%	5,672
African / African-American	0.0107%	9,369
South Asian	0.0055%	18,188
European (non-Finnish)	0.000509%	196,565

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.Pro1037Leu
Coding: c.3110C>T
MANE Select: NM_004448
dbSNP: rs201905649
Type: single nucleotide variant
Location: chr17:39726954 (GRCh38)
Gene constraint: LOEUF 0.518 · pLI 0.06 (gnomAD)
Structure: AlphaFold pLDDT 74.65 · 63 PDB
Residue 1037: the 'disordered' region

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.Pro1037= 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-pro1037leu (accessed [today's date]).

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