Is ERBB2 p.Pro1170Ala (c.3508C>G) pathogenic?

ERBB2 p.Pro1170Ala (c.3508C>G) is classified Benign in ERBB2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.096); Common (popmax 69.7%, mid) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about ERBB2 p.Pro1170Ala (c.3508C>G)?

AlphaMissense predicts likely benign (score 0.096) — an in-silico prediction, not a clinical call.

ERBB2 p.Pro1170Ala

Q: How common is ERBB2 p.Pro1170Ala (c.3508C>G) in the general population?

ERBB2 p.Pro1170Ala (c.3508C>G) is common (popmax 69.7%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.3508C>G · rs1058808 · VCV134082

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.096 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 69.7%, mid) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.096	likely benign
REVEL	0.254	benign-leaning
SaProt	LLR -7.02	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 5.9	GERP 2.4, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 1,215 bp · p 0.086 · regional, not allelic
Overall
CADD	24.6	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 69.7% Middle Eastern · 4,217/6,050 alleles

Filtering AF 68.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 68.6%

Overall 64.2% 1,034,902/1,612,086 alleles · common

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	77.1%	1
Middle Easterngrpmax	69.7%	1
South Asian	69.3%	1
Ashkenazi Jewishnot grpmax-eligible	68.4%	1
Finnishnot grpmax-eligible	67.7%	1
European (non-Finnish)	67.4%	1
Remaining individualsnot grpmax-eligible	62.5%	2
Admixed American	55.7%	2
East Asian	43.7%	2
African / African-American	22.5%	4

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro1170Ala
Coding: c.3508C>G
MANE Select: NM_004448
dbSNP: rs1058808
Type: single nucleotide variant
Location: chr17:39727784 (GRCh38)
Gene constraint: LOEUF 0.518 · pLI 0.06 (gnomAD)
Structure: AlphaFold pLDDT 74.65 · 63 PDB
Residue 1170: the 'disordered' region; a UniProt-annotated variant site (in)

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-pro1170ala (accessed [today's date]).

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