Is ERBB4 p.Lys681Arg (c.2042A>G) pathogenic?

ERBB4 p.Lys681Arg (c.2042A>G) is classified Uncertain significance in ERBB4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-07-18). AlphaMissense: likely benign (0.0784); Very rare (popmax 0.000339%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ERBB4 p.Lys681Arg (c.2042A>G)?

ERBB4 p.Lys681Arg (c.2042A>G) is associated with Inborn genetic diseases (ClinVar).

How common is ERBB4 p.Lys681Arg (c.2042A>G) in the general population?

ERBB4 p.Lys681Arg (c.2042A>G) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about ERBB4 p.Lys681Arg (c.2042A>G)?

AlphaMissense predicts likely benign (score 0.0784) — an in-silico prediction, not a clinical call.

ERBB4 p.Lys681Arg

c.2042A>G · VCV3509763

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0784 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0784	likely benign
REVEL	0.308	indeterminate
SaProt	LLR -6.64	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 2.1, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 210 kb · p 3.5e-09 · regional, not allelic
Overall
CADD	25.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000339% European (non-Finnish) · 4/1,179,594 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000274% 4/1,461,318 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: ERBB4
Protein: p.Lys681Arg
Coding: c.2042A>G
MANE Select: NM_005235
Type: single nucleotide variant
Location: chr2:211630499 (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.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
ERBB4 p.Lys291Arg Uncertain significance ★★ ⚠ same condition
ERBB4 p.Lys873Thr Uncertain significance ★★ ⚠ same condition
ERBB4 p.Met831Leu 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-lys681arg (accessed [today's date]).

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