Is ERBB2 p.Thr479Met (c.1436C>T) pathogenic?

ERBB2 p.Thr479Met (c.1436C>T) is classified Uncertain significance in ERBB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-10). AlphaMissense: likely benign (0.1421); Very rare (popmax 0.00517%, nfe).

How common is ERBB2 p.Thr479Met (c.1436C>T) in the general population?

ERBB2 p.Thr479Met (c.1436C>T) is very rare (popmax 0.00517%, nfe) (gnomAD).

What do computational predictors say about ERBB2 p.Thr479Met (c.1436C>T)?

AlphaMissense predicts likely benign (score 0.1421) — an in-silico prediction, not a clinical call.

ERBB2 p.Thr479Met

c.1436C>T · rs201021373 · VCV1419554

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1421 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00517%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1421	likely benign
REVEL	0.237	benign-leaning
SaProt	LLR -10.82	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.99 · evaluated, not missing
Constraint at this position
Conservation	phyloP 6	GERP 2.6, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 16 kb · p 1.3e-16 · regional, not allelic
Overall
CADD	26.3	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 0.00517% European (non-Finnish) · 61/1,180,022 alleles

Filtering AF 0.0041% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00372%

Overall 0.0044% 71/1,612,728 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00517%	19,345
Remaining individualsnot grpmax-eligible	0.0048%	20,834
South Asian	0.00439%	22,771
African / African-American	0.00266%	37,526
Admixed American	0.00167%	60,026

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.Thr479Met
Coding: c.1436C>T
MANE Select: NM_004448
dbSNP: rs201021373
Type: single nucleotide variant
Location: chr17:39715862 (GRCh38)
Gene constraint: LOEUF 0.518 · pLI 0.06 (gnomAD)
Structure: AlphaFold pLDDT 74.65 · 63 PDB
Residue 479: a turn; a disulfide bond

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

Similar variants

ERBB2 p.Thr479= 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-thr479met (accessed [today's date]).

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