Is ESPN p.Thr676Arg (c.2027C>G) pathogenic?

ESPN p.Thr676Arg (c.2027C>G) is classified Conflicting classifications of pathogenicity in ESPN (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-09-08). AlphaMissense: likely pathogenic (0.6196); Rare (popmax 0.304%, amr).

How common is ESPN p.Thr676Arg (c.2027C>G) in the general population?

ESPN p.Thr676Arg (c.2027C>G) is rare (popmax 0.304%, amr) (gnomAD).

What do computational predictors say about ESPN p.Thr676Arg (c.2027C>G)?

AlphaMissense predicts likely pathogenic (score 0.6196) — an in-silico prediction, not a clinical call.

ESPN p.Thr676Arg

c.2027C>G · rs771737095 · VCV517440

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.6196 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.304%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6196	likely pathogenic
REVEL	0.496	indeterminate
SaProt	LLR -6.00	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 0.43, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 11 kb · p 0.7 · regional, not allelic
Overall
CADD	26.6	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 0.304% Admixed American · 182/59,960 alleles

Filtering AF 0.267% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.254%

Overall 0.0114% 184/1,612,814 alleles · rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.304%	329
Remaining individualsnot grpmax-eligible	0.0032%	31,220

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.Thr676Arg
Coding: c.2027C>G
MANE Select: NM_031475
dbSNP: rs771737095
Type: single nucleotide variant
Location: chr1:6451714 (GRCh38)
Gene constraint: LOEUF 1.307 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.76
Residue 676: the 'disordered' region

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

Similar variants

ESPN p.Thr676Ala 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-thr676arg (accessed [today's date]).

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