Is ESPN c.*4C>T pathogenic?

ESPN c.4C>T is classified Likely benign in ESPN (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-08-20). Ultra-rare (popmax 0.0133%, amr); Associated with ESPN-related disorder.

What condition is associated with ESPN c.*4C>T?

ESPN c.*4C>T is associated with ESPN-related disorder (ClinVar).

How common is ESPN c.*4C>T in the general population?

ESPN c.*4C>T is ultra-rare (popmax 0.0133%, amr) (gnomAD).

ESPN c.*4C>T

rs376659285 · VCV3053343

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, amr)

Conditions

ESPN-related disorder

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 0.018	GERP -2.1
Non-coding constraint	Z 3.12	1 kb window · o/e 0.82 · regional · uncalibrated
Overall
CADD	3.944	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0133% Admixed American · 8/60,004 alleles

Filtering AF 0.00661% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00482%

Overall 0.0013% 21/1,610,124 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0133%	7,501
African / African-American	0.0107%	9,372
Remaining individualsnot grpmax-eligible	0.00803%	12,456

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
Coding: c.*4C>T
MANE Select: NM_031475
dbSNP: rs376659285
Type: single nucleotide variant
Location: chr1:6460150 (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

ESPN-related disorder

Similar variants

ESPN c.1464+1G>T Likely pathogenic ★ same condition
ESPN c.2062-1G>T Likely pathogenic ★ same condition
ESPN c.991-2A>G Likely pathogenic ★ same condition
ESPN p.Gln447Ter Likely pathogenic ★ same condition
ESPN p.Ser719Arg Likely pathogenic ★ ⚠ same condition
ESPN p.Arg791= Likely benign same condition
ESPN p.Pro430= Likely benign same condition
ESPN p.Thr429= Likely benign 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-c-star-4c-t (accessed [today's date]).

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