Is ESR1 p.Val458Leu (c.1372G>C) pathogenic?

ESR1 p.Val458Leu (c.1372G>C) is classified Uncertain significance in ESR1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-12). AlphaMissense: likely benign (0.2259); Absent from gnomAD v4.1.

How common is ESR1 p.Val458Leu (c.1372G>C) in the general population?

ESR1 p.Val458Leu (c.1372G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ESR1 p.Val458Leu (c.1372G>C)?

AlphaMissense predicts likely benign (score 0.2259) — an in-silico prediction, not a clinical call.

ESR1 p.Val458Leu

c.1372G>C · VCV4665394

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2259 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2259	likely benign
REVEL	0.261	benign-leaning
SaProt	LLR -6.62	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 5.1	GERP 0.85, phastCons 1
Regional constraint	o/e 0.49	unconstrained · MANE · 154 kb · p 2.8e-18 · regional, not allelic
Overall
CADD	18.78	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

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: ESR1
Protein: p.Val458Leu
Coding: c.1372G>C
MANE Select: NM_000125
Type: single nucleotide variant
Location: chr6:152094387 (GRCh38)
Gene constraint: LOEUF 0.456 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 67.14 · 492 PDB
Residue 458: the nr lbd domain; the 'interaction with akap13' region; the 'self-association' region; the 'transactivation af-2' region; a turn

Full ESR1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SYNE1 p.Arg8746Ter Pathogenic/Likely pathogenic ★★ same type
ESR1 p.Lys299Arg Uncertain significance ★★ ⚠ same type
SYNE1 p.Arg8735Leu Uncertain significance ★★ ⚠ same type
SYNE1 p.Arg8738His Uncertain significance ★★ ⚠ same type
SYNE1 p.Arg8746Gln Uncertain significance ★★ same type
SYNE1 p.Arg8782Gln Uncertain significance ★★ same type
SYNE1 p.Arg8782Gly Uncertain significance ★★ same type
SYNE1 p.Asp8725Asn 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/esr1-p-val458leu (accessed [today's date]).

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