Is ESPN p.Pro730Leu (c.2189C>T) pathogenic?

ESPN p.Pro730Leu (c.2189C>T) is classified Uncertain significance in ESPN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-25). AlphaMissense: likely benign (0.0933); Very rare (popmax 0.00667%, afr); Associated with Inborn genetic diseases.

What condition is associated with ESPN p.Pro730Leu (c.2189C>T)?

ESPN p.Pro730Leu (c.2189C>T) is associated with Inborn genetic diseases (ClinVar).

How common is ESPN p.Pro730Leu (c.2189C>T) in the general population?

ESPN p.Pro730Leu (c.2189C>T) is very rare (popmax 0.00667%, afr) (gnomAD).

What do computational predictors say about ESPN p.Pro730Leu (c.2189C>T)?

AlphaMissense predicts likely benign (score 0.0933) — an in-silico prediction, not a clinical call.

ESPN p.Pro730Leu

c.2189C>T · rs563809513 · VCV1523744

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0933 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0933	likely benign
REVEL	0.197	benign-leaning
SaProt	LLR -8.10	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 5.8	GERP 1.3, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 11 kb · p 0.7 · regional, not allelic
Overall
CADD	22.6	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

Grpmax group 0.00667% African / African-American · 5/75,008 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00161%

Overall 0.00149% 24/1,610,764 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00667%	15,002
Remaining individualsnot grpmax-eligible	0.00641%	15,588
Admixed American	0.00502%	19,931
South Asian	0.00111%	90,398
European (non-Finnish)	0.000933%	107,162

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: ESPN
Protein: p.Pro730Leu
Coding: c.2189C>T
MANE Select: NM_031475
dbSNP: rs563809513
Type: single nucleotide variant
Location: chr1:6451960 (GRCh38)
Gene constraint: LOEUF 1.307 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.76

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ESPN p.Ala139Thr Uncertain significance ★★ ⚠ same condition
ESPN p.Ala23Thr Uncertain significance ★★ ⚠ same condition
ESPN p.Ala484Thr Uncertain significance ★★ ⚠ same condition
ESPN p.Ala729Glu Uncertain significance ★★ ⚠ same condition
ESPN p.Arg113His Uncertain significance ★★ ⚠ same condition
ESPN p.Arg335Cys Uncertain significance ★★ ⚠ same condition
ESPN p.Arg339Gln Uncertain significance ★★ ⚠ same condition
ESPN p.Arg478Cys Uncertain significance ★★ ⚠ same condition

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/espn-p-pro730leu (accessed [today's date]).

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