Is ERBB2 p.Leu1061Pro (c.3182T>C) pathogenic?

ERBB2 p.Leu1061Pro (c.3182T>C) is classified Uncertain significance in ERBB2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-20). AlphaMissense: likely benign (0.0599); Rare (popmax 0.116%, mid); Associated with ovarian cancer.

What condition is associated with ERBB2 p.Leu1061Pro (c.3182T>C)?

ERBB2 p.Leu1061Pro (c.3182T>C) is associated with ovarian cancer, gastric cancer, lung cancer (ClinVar).

How common is ERBB2 p.Leu1061Pro (c.3182T>C) in the general population?

ERBB2 p.Leu1061Pro (c.3182T>C) is rare (popmax 0.116%, mid) (gnomAD).

What do computational predictors say about ERBB2 p.Leu1061Pro (c.3182T>C)?

AlphaMissense predicts likely benign (score 0.0599) — an in-silico prediction, not a clinical call.

ERBB2 p.Leu1061Pro

c.3182T>C · rs141142822 · VCV134079

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0599 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.116%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

ovarian cancer

Computational evidence

Protein change
AlphaMissense	0.0599	likely benign
REVEL	0.309	indeterminate
SaProt	LLR -6.11	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1	GERP 1.4, phastCons 0.2
Regional constraint	o/e 0.91	unconstrained · MANE · 1,215 bp · p 0.086 · regional, not allelic
Overall
CADD	21.0	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 0.116% Middle Eastern · 7/6,024 alleles

Filtering AF 0.0545% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0387%

Overall 0.0125% 202/1,612,946 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.116%	861
Ashkenazi Jewishnot grpmax-eligible	0.112%	895
Remaining individualsnot grpmax-eligible	0.0336%	2,973
Admixed American	0.0268%	3,725
European (non-Finnish)	0.01%	9,998
South Asian	0.0055%	18,194
African / African-American	0.00267%	37,467

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.Leu1061Pro
Coding: c.3182T>C
MANE Select: NM_004448
dbSNP: rs141142822
Type: single nucleotide variant
Location: chr17:39727317 (GRCh38)
Gene constraint: LOEUF 0.518 · pLI 0.06 (gnomAD)
Structure: AlphaFold pLDDT 74.65 · 63 PDB
Residue 1061: 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.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-leu1061pro (accessed [today's date]).

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