Is ERBB2 p.Arg756Ser (c.2268G>T) pathogenic?

ERBB2 p.Arg756Ser (c.2268G>T) is classified Uncertain significance in ERBB2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-12-26). AlphaMissense: likely pathogenic (0.9798); Very rare (popmax 0.000424%, nfe); Associated with colorectal cancer.

What condition is associated with ERBB2 p.Arg756Ser (c.2268G>T)?

ERBB2 p.Arg756Ser (c.2268G>T) is associated with colorectal cancer (ClinVar).

How common is ERBB2 p.Arg756Ser (c.2268G>T) in the general population?

ERBB2 p.Arg756Ser (c.2268G>T) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about ERBB2 p.Arg756Ser (c.2268G>T)?

AlphaMissense predicts likely pathogenic (score 0.9798) — an in-silico prediction, not a clinical call.

ERBB2 p.Arg756Ser

c.2268G>T · rs1435457852 · VCV1399145

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9798 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

colorectal cancer

Computational evidence

Protein change
AlphaMissense	0.9798	likely pathogenic
REVEL	0.599	indeterminate
SaProt	LLR -7.73	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP -4.6, phastCons 1
Regional constraint	o/e 0.48	unconstrained · MANE · 2,325 bp · p 1.2e-20 · regional, not allelic
Overall
CADD	21.4	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 0.000424% European (non-Finnish) · 5/1,180,008 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.00031% 5/1,613,924 alleles · very rare

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.Arg756Ser
Coding: c.2268G>T
MANE Select: NM_004448
dbSNP: rs1435457852
Type: single nucleotide variant
Location: chr17:39723971 (GRCh38)
Gene constraint: LOEUF 0.518 · pLI 0.06 (gnomAD)
Structure: AlphaFold pLDDT 74.65 · 63 PDB
Residue 756: the protein kinase domain

Full ERBB2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

colorectal cancer — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ERBB2 p.Gly537fs Pathogenic same condition
ERBB2 p.Pro1162fs Pathogenic same condition
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

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-arg756ser (accessed [today's date]).

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