Is ESPN p.Gln236Glu (c.706C>G) pathogenic?

ESPN p.Gln236Glu (c.706C>G) is classified Benign in ESPN (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-29). AlphaMissense: likely benign (0.0972); Common (popmax 12.6%, afr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about ESPN p.Gln236Glu (c.706C>G)?

AlphaMissense predicts likely benign (score 0.0972) — an in-silico prediction, not a clinical call.

ESPN p.Gln236Glu

Q: How common is ESPN p.Gln236Glu (c.706C>G) in the general population?

ESPN p.Gln236Glu (c.706C>G) is common (popmax 12.6%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.706C>G · rs6678405 · VCV508587

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0972 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 12.6%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0972	likely benign
REVEL	0.02	moderately benign-leaning
SaProt	LLR -7.93	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.47	acceptor loss, 3 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 1.6	GERP -1.6, phastCons 0.92
Regional constraint	o/e 0.88	unconstrained · MANE · 21 kb · p 0.002 · regional, not allelic
Overall
CADD	22.7	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 12.6% African / African-American · 8,861/70,500 alleles

Filtering AF 12.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 12.3%

Overall 0.664% 10,117/1,524,536 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	12.6%	8
Admixed American	0.933%	107
Remaining individualsnot grpmax-eligible	0.878%	114
Middle Eastern	0.742%	135
South Asian	0.0279%	3,583
European (non-Finnish)	0.018%	5,554

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.Gln236Glu
Coding: c.706C>G
MANE Select: NM_031475
dbSNP: rs6678405
Type: single nucleotide variant
Location: chr1:6440656 (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-gln236glu (accessed [today's date]).

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