Is ESPN p.Ile681= (c.2043C>T) pathogenic?

ESPN p.Ile681= (c.2043C>T) is classified Likely benign in ESPN (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-15). Very rare (popmax 0.00879%, sas).

How common is ESPN p.Ile681= (c.2043C>T) in the general population?

ESPN p.Ile681= (c.2043C>T) is very rare (popmax 0.00879%, sas) (gnomAD).

ESPN p.Ile681=

c.2043C>T · rs371653062 · VCV1649694

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00879%, sas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.301	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.6	GERP -3
Overall
CADD	5.381	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00879% South Asian · 8/90,974 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00312%

Overall 0.00211% 34/1,612,470 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00879%	11,372
Admixed American	0.00334%	29,962
European (non-Finnish)	0.00178%	56,182
Remaining individualsnot grpmax-eligible	0.0016%	62,388
Finnishnot grpmax-eligible	0.00159%	63,048
African / African-American	0.00133%	74,944

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.Ile681=
Coding: c.2043C>T
MANE Select: NM_031475
dbSNP: rs371653062
Type: single nucleotide variant
Location: chr1:6451730 (GRCh38)
Gene constraint: LOEUF 1.307 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.76
Residue 681: the 'disordered' region

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

Similar variants

ESPN p.Ile681Met Uncertain significance ★ same residue
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

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-ile681 (accessed [today's date]).

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