Is ESX1 p.Pro320Arg (c.959C>G) pathogenic?

ESX1 p.Pro320Arg (c.959C>G) is classified Benign in ESX1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2017-05-30). AlphaMissense: likely benign (0.1313); Common (popmax 10.4%, afr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about ESX1 p.Pro320Arg (c.959C>G)?

AlphaMissense predicts likely benign (score 0.1313) — an in-silico prediction, not a clinical call.

ESX1 p.Pro320Arg

Q: How common is ESX1 p.Pro320Arg (c.959C>G) in the general population?

ESX1 p.Pro320Arg (c.959C>G) is common (popmax 10.4%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.959C>G · rs191202058 · VCV778984

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1313 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 10.4%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1313	likely benign
REVEL	0.15	moderately benign-leaning
SaProt	LLR -4.93	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 -0.21	GERP -1.4
Regional constraint	o/e 0.40	unconstrained · MANE · 310 bp · p 9.9e-11 · regional, not allelic
Overall
CADD	3.273	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 10.4% African / African-American · 4,051/38,920 alleles

Filtering AF 10.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 10%

Overall 5.54% 44,166/797,198 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	10.4%	10
East Asian	9.56%	10
Admixed American	7.4%	14
South Asian	5.96%	17
Remaining individualsnot grpmax-eligible	5.65%	18
European (non-Finnish)	5.25%	19
Middle Eastern	3.71%	27
Ashkenazi Jewishnot grpmax-eligible	3.36%	30
Finnishnot grpmax-eligible	2.74%	37
Amishnot grpmax-eligible	0.792%	126

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.Pro320Arg
Coding: c.959C>G
MANE Select: NM_153448
dbSNP: rs191202058
Type: single nucleotide variant
Location: chrX:104250490 (GRCh38)
Structure: AlphaFold pLDDT 62.35
Residue 320: 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.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
ESX1 p.Ala402Val Uncertain significance ★ ⚠ same type
ESX1 p.Ala57Val 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-pro320arg (accessed [today's date]).

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