Is ESPN p.Pro570Ser (c.1708C>T) pathogenic?

ESPN p.Pro570Ser (c.1708C>T) is classified Uncertain significance in ESPN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-09-17). AlphaMissense: likely benign (0.0744); Very rare (popmax 0.00325%, eas).

How common is ESPN p.Pro570Ser (c.1708C>T) in the general population?

ESPN p.Pro570Ser (c.1708C>T) is very rare (popmax 0.00325%, eas) (gnomAD).

What do computational predictors say about ESPN p.Pro570Ser (c.1708C>T)?

AlphaMissense predicts likely benign (score 0.0744) — an in-silico prediction, not a clinical call.

ESPN p.Pro570Ser

c.1708C>T · rs1396313792 · VCV1482647

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0744 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00325%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0744	likely benign
REVEL	0.067	moderately benign-leaning
SaProt	LLR -6.43	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.025	GERP 0.25, phastCons 0.23
Regional constraint	o/e 0.58	unconstrained · MANE · 3,146 bp · p 3.4e-10 · regional, not allelic
Overall
CADD	16.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00325% East Asian · 1/30,734 alleles

Filtering AF 0.000864% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000685%

Overall 0.00121% 16/1,324,176 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00325%	30,734
European (non-Finnish)	0.00144%	69,477

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.Pro570Ser
Coding: c.1708C>T
MANE Select: NM_031475
dbSNP: rs1396313792
Type: single nucleotide variant
Location: chr1:6448884 (GRCh38)
Gene constraint: LOEUF 1.307 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.76
Residue 570: the 'disordered' region

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

Similar variants

ESPN p.Pro570Leu Benign/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-pro570ser (accessed [today's date]).

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