Is ESX1 p.Pro289Ser (c.865C>T) pathogenic?

ESX1 p.Pro289Ser (c.865C>T) is classified Likely benign in ESX1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-01). AlphaMissense: likely benign (0.1013); Very rare (popmax 0.00905%, eas).

How common is ESX1 p.Pro289Ser (c.865C>T) in the general population?

ESX1 p.Pro289Ser (c.865C>T) is very rare (popmax 0.00905%, eas) (gnomAD).

What do computational predictors say about ESX1 p.Pro289Ser (c.865C>T)?

AlphaMissense predicts likely benign (score 0.1013) — an in-silico prediction, not a clinical call.

ESX1 p.Pro289Ser

c.865C>T · rs141524947 · VCV2661114

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1013 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00905%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1013	likely benign
REVEL	0.239	benign-leaning
SaProt	LLR -10.16	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.067	GERP 0.56
Regional constraint	o/e 0.73	unconstrained · MANE · 3,709 bp · p 0.0011 · regional, not allelic
Overall
CADD	2.611	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 0.00905% East Asian · 3/33,162 alleles

Filtering AF 0.00413% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0037%

Overall 0.00433% 51/1,178,044 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00905%	11,054
European (non-Finnish)	0.00536%	18,652
African / African-American	0.00177%	56,476

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: ESX1
Protein: p.Pro289Ser
Coding: c.865C>T
MANE Select: NM_153448
dbSNP: rs141524947
Type: single nucleotide variant
Location: chrX:104250584 (GRCh38)
Structure: AlphaFold pLDDT 62.35
Residue 289: the '15 x 9 aa tandem repeats of p-p-x-x-p-x-p-p-x' region

Full ESX1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ESX1 p.Pro289= Likely benign ★ same residue
ESX1 p.Pro320Arg Benign ★★ same type
ESX1 p.Trp297Gly Likely benign ★★ same type
ESX1 p.Pro365Arg Likely pathogenic ★ ⚠ same type
ESX1 p.Ala292Val Uncertain significance ★ ⚠ same type
ESX1 p.Ala301Thr Uncertain significance ★ ⚠ same type
ESX1 p.Ala319Val Uncertain significance ★ ⚠ same type
ESX1 p.Ala337Glu 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/esx1-p-pro289ser (accessed [today's date]).

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