Is ESPN p.Gln756His (c.2268G>C) pathogenic?

ESPN p.Gln756His (c.2268G>C) is classified Uncertain significance in ESPN (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-30). AlphaMissense: likely pathogenic (0.8544); Very rare (popmax 0.00354%, amr); Associated with Inborn genetic diseases.

What condition is associated with ESPN p.Gln756His (c.2268G>C)?

ESPN p.Gln756His (c.2268G>C) is associated with Inborn genetic diseases (ClinVar).

How common is ESPN p.Gln756His (c.2268G>C) in the general population?

ESPN p.Gln756His (c.2268G>C) is very rare (popmax 0.00354%, amr) (gnomAD).

What do computational predictors say about ESPN p.Gln756His (c.2268G>C)?

AlphaMissense predicts likely pathogenic (score 0.8544) — an in-silico prediction, not a clinical call.

ESPN p.Gln756His

c.2268G>C · VCV3510362

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8544 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00354%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8544	likely pathogenic
REVEL	0.489	indeterminate
SaProt	LLR -12.39	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.7	GERP -0.75, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 11 kb · p 0.7 · regional, not allelic
Overall
CADD	25.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00354% Admixed American · 2/56,418 alleles

Filtering AF 0.000588% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00022%

Overall 0.000189% 3/1,583,656 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00354%	28,209
European (non-Finnish)	8.59e-05%	1,164,108

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.Gln756His
Coding: c.2268G>C
MANE Select: NM_031475
Type: single nucleotide variant
Location: chr1:6452039 (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.Gln756Arg Uncertain significance ★ ⚠ same residue
ESPN p.Gln756Glu Conflicting classifications of pathogenicity ★ ⚠ same residue
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

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-gln756his (accessed [today's date]).

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