Is ERBB2 p.Asp1252Asn (c.3754G>A) pathogenic?

ERBB2 p.Asp1252Asn (c.3754G>A) is classified Uncertain significance in ERBB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-13). AlphaMissense: likely benign (0.0861); Ultra-rare (popmax 0.0642%, afr).

How common is ERBB2 p.Asp1252Asn (c.3754G>A) in the general population?

ERBB2 p.Asp1252Asn (c.3754G>A) is ultra-rare (popmax 0.0642%, afr) (gnomAD).

What do computational predictors say about ERBB2 p.Asp1252Asn (c.3754G>A)?

AlphaMissense predicts likely benign (score 0.0861) — an in-silico prediction, not a clinical call.

ERBB2 p.Asp1252Asn

c.3754G>A · rs184203026 · VCV1397430

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0861 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0642%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0861	likely benign
REVEL	0.215	benign-leaning
SaProt	LLR -6.77	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.7	GERP 2.1, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 1,215 bp · p 0.086 · regional, not allelic
Overall
CADD	22.4	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 0.0642% African / African-American · 48/74,732 alleles

Filtering AF 0.0497% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0446%

Overall 0.00314% 50/1,593,556 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0642%	1,557
Remaining individualsnot grpmax-eligible	0.00324%	30,874

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: ERBB2
Protein: p.Asp1252Asn
Coding: c.3754G>A
MANE Select: NM_004448
dbSNP: rs184203026
Type: single nucleotide variant
Location: chr17:39728030 (GRCh38)
Gene constraint: LOEUF 0.518 · pLI 0.06 (gnomAD)
Structure: AlphaFold pLDDT 74.65 · 63 PDB
Residue 1252: the 'disordered' region

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

Similar variants

ERBB2 p.Asp1252= Likely benign ★ same residue
ERBB2 p.Ala598Asp Uncertain significance ★★ ⚠ same type
ERBB2 p.Ala644Thr Uncertain significance ★★ ⚠ same type
ERBB2 p.Arg1048Cys Uncertain significance ★★ ⚠ same type
ERBB2 p.Arg188Cys Uncertain significance ★★ ⚠ same type
ERBB2 p.Arg188His Uncertain significance ★★ ⚠ same type
ERBB2 p.Arg190Gln Uncertain significance ★★ ⚠ same type
ERBB2 p.Arg203His Uncertain significance ★★ ⚠ 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/erbb2-p-asp1252asn (accessed [today's date]).

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