Is ERBB4 p.Arg72Pro (c.215G>C) pathogenic?

ERBB4 p.Arg72Pro (c.215G>C) is classified Likely benign in ERBB4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-08-31). AlphaMissense: likely pathogenic (0.9242); Ultra-rare (popmax 0.0733%, amr); Associated with Inborn genetic diseases.

What condition is associated with ERBB4 p.Arg72Pro (c.215G>C)?

ERBB4 p.Arg72Pro (c.215G>C) is associated with Inborn genetic diseases (ClinVar).

How common is ERBB4 p.Arg72Pro (c.215G>C) in the general population?

ERBB4 p.Arg72Pro (c.215G>C) is ultra-rare (popmax 0.0733%, amr) (gnomAD).

What do computational predictors say about ERBB4 p.Arg72Pro (c.215G>C)?

AlphaMissense predicts likely pathogenic (score 0.9242) — an in-silico prediction, not a clinical call.

ERBB4 p.Arg72Pro

c.215G>C · rs762478821 · VCV2201054

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9242 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0733%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9242	likely pathogenic
REVEL	0.685	pathogenic-leaning
SaProt	LLR -13.36	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP -1.5, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 836 kb · p 7.9e-10 · regional, not allelic
Overall
CADD	32.0	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 0.0733% Admixed American · 44/59,998 alleles

Filtering AF 0.0561% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.05%

Overall 0.00279% 45/1,614,032 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0733%	1,364
Remaining individualsnot grpmax-eligible	0.0016%	62,482

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: ERBB4
Protein: p.Arg72Pro
Coding: c.215G>C
MANE Select: NM_005235
dbSNP: rs762478821
Type: single nucleotide variant
Location: chr2:212124771 (GRCh38)
Gene constraint: LOEUF 0.357 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 73.17 · 14 PDB

Full ERBB4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ERBB4 p.Arg72Trp Uncertain significance ★ ⚠ same residue
ERBB4 p.Arg72= Likely benign ★ same residue
ERBB4 p.Arg72Gln Uncertain significance ⚠ same residue
ERBB4 p.Arg393Gln Uncertain significance ★★ ⚠ same condition
ERBB4 p.Gln598Lys Uncertain significance ★★ same condition
ERBB4 p.Glu1138Gly Uncertain significance ★★ ⚠ same condition
ERBB4 p.Glu696Ala Uncertain significance ★★ ⚠ same condition
ERBB4 p.Ile337Val Uncertain significance ★★ ⚠ 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/erbb4-p-arg72pro (accessed [today's date]).

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