Is ERBB2 p.Arg1111Trp (c.3331C>T) pathogenic?

ERBB2 p.Arg1111Trp (c.3331C>T) is classified Uncertain significance in ERBB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-14). AlphaMissense: ambiguous (0.4977); Very rare (popmax 0.00223%, eas).

How common is ERBB2 p.Arg1111Trp (c.3331C>T) in the general population?

ERBB2 p.Arg1111Trp (c.3331C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about ERBB2 p.Arg1111Trp (c.3331C>T)?

AlphaMissense predicts ambiguous (score 0.4977) — an in-silico prediction, not a clinical call.

ERBB2 p.Arg1111Trp

c.3331C>T · rs143958183 · VCV1354723

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4977 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4977	ambiguous
REVEL	0.807	moderately pathogenic-leaning
SaProt	LLR -8.33	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.72 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.9	GERP 1.3, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 1,215 bp · p 0.086 · regional, not allelic
Overall
CADD	28.8	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 0.00223% East Asian · 1/44,882 alleles

Filtering AF 0.000689% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000539%

Overall 0.00106% 17/1,609,584 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,882
Remaining individualsnot grpmax-eligible	0.00161%	62,302
Finnishnot grpmax-eligible	0.00156%	64,000
European (non-Finnish)	0.00119%	84,187

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.Arg1111Trp
Coding: c.3331C>T
MANE Select: NM_004448
dbSNP: rs143958183
Type: single nucleotide variant
Location: chr17:39727466 (GRCh38)
Gene constraint: LOEUF 0.518 · pLI 0.06 (gnomAD)
Structure: AlphaFold pLDDT 74.65 · 63 PDB
Residue 1111: the 'disordered' region

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

Similar variants

ERBB2 p.Arg1111Gln Uncertain significance ★ ⚠ 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-arg1111trp (accessed [today's date]).

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