Is ESPN p.Pro275Ala (c.823C>G) pathogenic?

ESPN p.Pro275Ala (c.823C>G) is classified Conflicting classifications of pathogenicity in ESPN (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-03-01). AlphaMissense: ambiguous (0.4859); Rare (popmax 0.166%, mid).

How common is ESPN p.Pro275Ala (c.823C>G) in the general population?

ESPN p.Pro275Ala (c.823C>G) is rare (popmax 0.166%, mid) (gnomAD).

What do computational predictors say about ESPN p.Pro275Ala (c.823C>G)?

AlphaMissense predicts ambiguous (score 0.4859) — an in-silico prediction, not a clinical call.

ESPN p.Pro275Ala

c.823C>G · rs3817921 · VCV1048984

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4859 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.166%, mid)

Computational evidence

Protein change
AlphaMissense	0.4859	ambiguous
REVEL	0.341	indeterminate
SaProt	LLR -8.91	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 1.7, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 21 kb · p 0.002 · regional, not allelic
Overall
CADD	24.6	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 0.166% Middle Eastern · 7/4,216 alleles

Filtering AF 0.0779% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0552%

Overall 0.0319% 432/1,354,968 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.166%	602
Ashkenazi Jewishnot grpmax-eligible	0.105%	956
Admixed American	0.0674%	1,483
Remaining individualsnot grpmax-eligible	0.0411%	2,432
South Asian	0.0287%	3,482
East Asian	0.0263%	3,803
European (non-Finnish)	0.0248%	4,027
African / African-American	0.0244%	4,097
Finnishnot grpmax-eligible	0.0197%	5,083

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.Pro275Ala
Coding: c.823C>G
MANE Select: NM_031475
dbSNP: rs3817921
Type: single nucleotide variant
Location: chr1:6440773 (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 p.Pro275= Likely benign ★ 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-pro275ala (accessed [today's date]).

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