Is ERBB2 p.Ser653Phe (c.1958C>T) pathogenic?

ERBB2 p.Ser653Phe (c.1958C>T) is classified Pathogenic in ERBB2 (ClinVar, No assertion criteria, 1 submitter). AlphaMissense: likely benign (0.1933); Absent from gnomAD v4.1; Associated with urinary bladder cancer.

What condition is associated with ERBB2 p.Ser653Phe (c.1958C>T)?

ERBB2 p.Ser653Phe (c.1958C>T) is associated with urinary bladder cancer (ClinVar).

How common is ERBB2 p.Ser653Phe (c.1958C>T) in the general population?

ERBB2 p.Ser653Phe (c.1958C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ERBB2 p.Ser653Phe (c.1958C>T)?

AlphaMissense predicts likely benign (score 0.1933) — an in-silico prediction, not a clinical call.

ERBB2 p.Ser653Phe

c.1958C>T · rs2145802334 · VCV2582289

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1933 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

urinary bladder cancer

Computational evidence

Protein change
AlphaMissense	0.1933	likely benign ⚠ discordant with ClinVar
REVEL	0.229	benign-leaning
SaProt	LLR -8.88	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 5	GERP 0.43, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 16 kb · p 1.3e-16 · regional, not allelic
Overall
CADD	22.0	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.Ser653Phe
Coding: c.1958C>T
MANE Select: NM_004448
dbSNP: rs2145802334
Type: single nucleotide variant
Location: chr17:39723330 (GRCh38)
Gene constraint: LOEUF 0.518 · pLI 0.06 (gnomAD)
Structure: AlphaFold pLDDT 74.65 · 63 PDB
Residue 653: an α-helix

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

Disease context

urinary bladder cancer — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ERBB2 p.Gly309Arg Pathogenic same condition
ERBB2 p.Gly309Glu Pathogenic same condition
ERBB2 p.Val697Met Pathogenic same condition
ERBB2 p.Val839Met Pathogenic ⚠ same condition
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

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-ser653phe (accessed [today's date]).

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