Is ERBB2 p.Ala710Val (c.2129C>T) pathogenic?

ERBB2 p.Ala710Val (c.2129C>T) is classified Pathogenic in ERBB2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-09-25). AlphaMissense: likely pathogenic (0.9196); Absent from gnomAD v4.1; Associated with visceral neuropathy, familial, 2, autosomal recessive.

What condition is associated with ERBB2 p.Ala710Val (c.2129C>T)?

ERBB2 p.Ala710Val (c.2129C>T) is associated with visceral neuropathy, familial, 2, autosomal recessive (ClinVar).

How common is ERBB2 p.Ala710Val (c.2129C>T) in the general population?

ERBB2 p.Ala710Val (c.2129C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ERBB2 p.Ala710Val (c.2129C>T)?

AlphaMissense predicts likely pathogenic (score 0.9196) — an in-silico prediction, not a clinical call.

ERBB2 p.Ala710Val

c.2129C>T · rs2145813505 · VCV1188812

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9196 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

visceral neuropathy, familial, 2, autosomal recessive

Computational evidence

Protein change
AlphaMissense	0.9196	likely pathogenic ✓ concordant with ClinVar
REVEL	0.603	indeterminate
SaProt	LLR -7.64	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	Δ0.29	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 7.7	GERP -1.1, phastCons 1
Regional constraint	o/e 0.48	unconstrained · MANE · 2,325 bp · p 1.2e-20 · regional, not allelic
Overall
CADD	34.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ERBB2
Protein: p.Ala710Val
Coding: c.2129C>T
MANE Select: NM_004448
dbSNP: rs2145813505
Type: single nucleotide variant
Location: chr17:39723581 (GRCh38)
Gene constraint: LOEUF 0.518 · pLI 0.06 (gnomAD)
Structure: AlphaFold pLDDT 74.65 · 63 PDB
Residue 710: a UniProt-annotated variant site (in vscn2; almost complete loss of erbb2 and erbb3 phosphorylation in the presence or in the absence of nrg1 stimulation, suggesting alteration of downstream signaling; does not affect the subcellular localization at the cell membrane)

Full ERBB2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

visceral neuropathy, familial, 2, autosomal recessive — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ERBB2 p.Ala710= Likely benign ★ same residue
ERBB2 p.Ala598Asp Uncertain significance ★★ ⚠ same condition
ERBB2 p.Arg1048Cys Uncertain significance ★★ ⚠ same condition
ERBB2 p.Arg188Cys Uncertain significance ★★ ⚠ same condition
ERBB2 p.Arg190Gln Uncertain significance ★★ ⚠ same condition
ERBB2 p.Arg203His Uncertain significance ★★ ⚠ same condition
ERBB2 p.Arg217Cys Uncertain significance ★★ ⚠ same condition
ERBB2 p.Arg517Gln 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/erbb2-p-ala710val (accessed [today's date]).

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