Is ERBB3 p.Ser1097Pro (c.3289T>C) pathogenic?

ERBB3 p.Ser1097Pro (c.3289T>C) is classified Likely benign in ERBB3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-05). AlphaMissense: likely benign (0.1501); Rare (popmax 0.33%, mid).

How common is ERBB3 p.Ser1097Pro (c.3289T>C) in the general population?

ERBB3 p.Ser1097Pro (c.3289T>C) is rare (popmax 0.33%, mid) (gnomAD).

What do computational predictors say about ERBB3 p.Ser1097Pro (c.3289T>C)?

AlphaMissense predicts likely benign (score 0.1501) — an in-silico prediction, not a clinical call.

ERBB3 p.Ser1097Pro

c.3289T>C · rs77822103 · VCV713417

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1501 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.33%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1501	likely benign
REVEL	0.418	indeterminate
SaProt	LLR -8.00	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.8, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 2,180 bp · p 0.066 · regional, not allelic
Overall
CADD	25.5	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 0.33% Middle Eastern · 20/6,062 alleles

Filtering AF 0.219% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.198%

Overall 0.0429% 693/1,614,084 alleles · rare exomes 516/1,461,886 · genomes 177/152,198 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.33%	303
African / African-American	0.237%	421
Admixed American	0.182%	550
Remaining individualsnot grpmax-eligible	0.0944%	1,060
Ashkenazi Jewishnot grpmax-eligible	0.054%	1,850
European (non-Finnish)	0.0261%	3,831
East Asian	0.00223%	44,878
Finnishnot grpmax-eligible	0.00156%	64,026
South Asian	0.0011%	91,074

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: ERBB3
Protein: p.Ser1097Pro
Coding: c.3289T>C
MANE Select: NM_001982
dbSNP: rs77822103
Type: single nucleotide variant
Location: chr12:56101148 (GRCh38)
Gene constraint: LOEUF 0.695 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.90 · 23 PDB
Residue 1097: the 'disordered' region

Full ERBB3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ERBB3 p.Ile703Leu Uncertain significance ★★ ⚠ same type
ERBB3 p.Lys747Asn Uncertain significance ★★ ⚠ same type
ERBB3 p.Pro1142Leu Uncertain significance ★★ ⚠ same type
ERBB3 p.Pro238Leu Uncertain significance ★★ ⚠ same type
ERBB3 p.Trp373Arg Uncertain significance ★★ ⚠ same type
ERBB3 c.1109+202A>G Likely benign ★★ same type
ERBB3 c.1109+207G>A Benign ★★ same type
ERBB3 c.1860-128G>A Benign ★★ 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/erbb3-p-ser1097pro (accessed [today's date]).

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