Is ESR1 p.Ser118Pro (c.352T>C) pathogenic?

ESR1 p.Ser118Pro (c.352T>C) is classified Benign/Likely benign in ESR1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-01). AlphaMissense: likely benign (0.0835); Rare (popmax 0.476%, nfe).

How common is ESR1 p.Ser118Pro (c.352T>C) in the general population?

ESR1 p.Ser118Pro (c.352T>C) is rare (popmax 0.476%, nfe) (gnomAD).

What do computational predictors say about ESR1 p.Ser118Pro (c.352T>C)?

AlphaMissense predicts likely benign (score 0.0835) — an in-silico prediction, not a clinical call.

ESR1 p.Ser118Pro

c.352T>C · rs200075329 · VCV790988

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0835 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.476%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0835	likely benign
REVEL	0.152	moderately benign-leaning
SaProt	LLR -5.92	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 6	GERP 1.4, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 35 kb · p 0.76 · regional, not allelic
Overall
CADD	23.9	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 0.476% European (non-Finnish) · 5,557/1,166,348 alleles

Filtering AF 0.466% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.462%

Overall 0.449% 7,108/1,584,834 alleles · rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	1.66%	60
European (non-Finnish)grpmax	0.476%	210
Admixed American	0.406%	246
Remaining individualsnot grpmax-eligible	0.38%	263
Middle Eastern	0.0703%	1,423
African / African-American	0.0657%	1,523
South Asian	0.0426%	2,349
Ashkenazi Jewishnot grpmax-eligible	0.00697%	14,356

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: ESR1
Protein: p.Ser118Pro
Coding: c.352T>C
MANE Select: NM_000125
dbSNP: rs200075329
Type: single nucleotide variant
Location: chr6:151808264 (GRCh38)
Gene constraint: LOEUF 0.456 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 67.14 · 492 PDB
Residue 118: a modified residue (phosphoserine); the 'modulating (transactivation af-1); mediates interaction with macrod1' region; the 'interaction with ddx5; self-association' region

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-ser118pro (accessed [today's date]).

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