Is ERBB3 p.Arg1116= (c.3348G>A) pathogenic?

ERBB3 p.Arg1116= (c.3348G>A) is classified Benign in ERBB3 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-28). Common (popmax 40.2%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with visceral neuropathy, familial.

What condition is associated with ERBB3 p.Arg1116= (c.3348G>A)?

ERBB3 p.Arg1116= (c.3348G>A) is associated with visceral neuropathy, familial, lethal congenital contracture syndrome 2 (ClinVar).

ERBB3 p.Arg1116=

Q: How common is ERBB3 p.Arg1116= (c.3348G>A) in the general population?

ERBB3 p.Arg1116= (c.3348G>A) is common (popmax 40.2%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.3348G>A · rs2271189 · VCV1248586

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Common

common (popmax 40.2%, nfe) — too common for a highly-penetrant pathogenic allele

Conditions

visceral neuropathy, familial

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.6	GERP -3.6
Overall
CADD	1.773	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 40.2% European (non-Finnish) · 474,028/1,179,776 alleles

Filtering AF 40.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 40%

Overall 37.3% 602,025/1,613,462 alleles · common exomes 555,279/1,461,766 · genomes 46,746/151,696 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	50.4%	2
European (non-Finnish)grpmax	40.2%	2
Finnishnot grpmax-eligible	38.5%	3
Ashkenazi Jewishnot grpmax-eligible	37%	3
Remaining individualsnot grpmax-eligible	35.8%	3
Admixed American	35.2%	3
East Asian	31.9%	3
Middle Eastern	26.3%	4
South Asian	25.8%	4
African / African-American	12.1%	8

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: ERBB3
Protein: p.Arg1116=
Coding: c.3348G>A
MANE Select: NM_001982
dbSNP: rs2271189
Type: single nucleotide variant
Location: chr12:56101207 (GRCh38)
Gene constraint: LOEUF 0.695 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.90 · 23 PDB
Residue 1116: the 'disordered' region

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

Disease context

visceral neuropathy, familial — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: lethal congenital contracture syndrome 2

Similar variants

ERBB3 p.Lys747Asn Uncertain significance ★★ ⚠ same condition
ERBB3 p.Pro1142Leu Uncertain significance ★★ ⚠ same condition
ERBB3 c.234+8A>T Benign ★★ same condition
ERBB3 c.2616+16G>C Benign/Likely benign ★★ same condition
ERBB3 c.3129+9A>C Benign ★★ same condition
ERBB3 c.1184-9A>G Likely pathogenic ★ same condition
ERBB3 c.3202-2A>G Likely pathogenic ★ same condition
ERBB3 c.83-2A>G Likely pathogenic ★ 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/erbb3-p-arg1116 (accessed [today's date]).

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