Is ESPN p.Leu18= (c.52C>T) pathogenic?

ESPN p.Leu18= (c.52C>T) is classified Likely benign in ESPN (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-16). Very rare (popmax 0.00241%, amr).

How common is ESPN p.Leu18= (c.52C>T) in the general population?

ESPN p.Leu18= (c.52C>T) is very rare (popmax 0.00241%, amr) (gnomAD).

ESPN p.Leu18=

c.52C>T · VCV3685526

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00241%, amr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.5	GERP -2.4, phastCons 1
Overall
CADD	15.38	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00241% Admixed American · 1/41,570 alleles

Overall 7.6e-05% 1/1,315,806 alleles · very rare

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.Leu18=
Coding: c.52C>T
MANE Select: NM_031475
Type: single nucleotide variant
Location: chr1:6425007 (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

Similar variants

ESPN c.1464+1G>A Likely pathogenic ★★ same type
ESPN p.Ala139Thr Uncertain significance ★★ ⚠ same type
ESPN p.Ala23Thr Uncertain significance ★★ ⚠ same type
ESPN p.Ala484Thr Uncertain significance ★★ ⚠ same type
ESPN p.Ala591Val Uncertain significance ★★ ⚠ same type
ESPN p.Ala610Pro Uncertain significance ★★ ⚠ same type
ESPN p.Ala624Thr Uncertain significance ★★ ⚠ same type
ESPN p.Ala729Glu 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/espn-p-leu18 (accessed [today's date]).

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