Is ERBB3 p.Ile449= (c.1347T>C) pathogenic?

ERBB3 p.Ile449= (c.1347T>C) is classified Benign in ERBB3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-31). Common (popmax 7.86%, nfe) — too common for a highly-penetrant pathogenic allele.

ERBB3 p.Ile449=

Q: How common is ERBB3 p.Ile449= (c.1347T>C) in the general population?

ERBB3 p.Ile449= (c.1347T>C) is common (popmax 7.86%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1347T>C · rs2229046 · VCV1269955

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Common

common (popmax 7.86%, nfe) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -4.2	GERP -3.7
Overall
CADD	1.734	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 7.86% European (non-Finnish) · 92,742/1,179,840 alleles

Filtering AF 7.82% ClinGen BA1/BS1 input FAF95, joint · FAF99 7.8%

Overall 7.4% 119,491/1,613,794 alleles · common exomes 108,389/1,461,692 · genomes 11,102/152,102 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	9.88%	10
Amishnot grpmax-eligible	8.9%	11
European (non-Finnish)grpmax	7.86%	13
African / African-American	7.81%	13
Ashkenazi Jewishnot grpmax-eligible	7.19%	14
Remaining individualsnot grpmax-eligible	7%	14
Middle Eastern	6.35%	16
South Asian	5.35%	19
Admixed American	4.5%	22
East Asian	0.058%	1,726

Finnish 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: ERBB3
Protein: p.Ile449=
Coding: c.1347T>C
MANE Select: NM_001982
dbSNP: rs2229046
Type: single nucleotide variant
Location: chr12:56093417 (GRCh38)
Gene constraint: LOEUF 0.695 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.90 · 23 PDB

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-ile449 (accessed [today's date]).

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