Is ERBB2 p.Leu16Phe (c.48G>T) pathogenic?

ERBB2 p.Leu16Phe (c.48G>T) is classified Uncertain significance in ERBB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-10). AlphaMissense: likely benign (0.0711); Very rare (popmax 0.00631%, nfe).

How common is ERBB2 p.Leu16Phe (c.48G>T) in the general population?

ERBB2 p.Leu16Phe (c.48G>T) is very rare (popmax 0.00631%, nfe) (gnomAD).

What do computational predictors say about ERBB2 p.Leu16Phe (c.48G>T)?

AlphaMissense predicts likely benign (score 0.0711) — an in-silico prediction, not a clinical call.

ERBB2 p.Leu16Phe

c.48G>T · VCV3710473

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0711 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00631%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0711	likely benign
REVEL	0.416	indeterminate
SaProt	LLR -10.40	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.2	GERP 1.8, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 6,883 bp · p 0.54 · regional, not allelic
Overall
CADD	22.3	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 0.00631% European (non-Finnish) · 69/1,093,206 alleles

Filtering AF 0.00507% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00465%

Overall 0.00497% 71/1,429,048 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00631%	15,844
Remaining individualsnot grpmax-eligible	0.00366%	27,349

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.Leu16Phe
Coding: c.48G>T
MANE Select: NM_004448
Type: single nucleotide variant
Location: chr17:39700286 (GRCh38)
Gene constraint: LOEUF 0.518 · pLI 0.06 (gnomAD)
Structure: AlphaFold pLDDT 74.65 · 63 PDB

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

Similar variants

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
ERBB2 p.Arg217Cys 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-leu16phe (accessed [today's date]).

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