Is ESPN p.Arg19Lys (c.56G>A) pathogenic?

ESPN p.Arg19Lys (c.56G>A) is classified Uncertain significance in ESPN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-06-13). AlphaMissense: likely benign (0.0781); Ultra-rare (popmax 0.0103%, afr).

How common is ESPN p.Arg19Lys (c.56G>A) in the general population?

ESPN p.Arg19Lys (c.56G>A) is ultra-rare (popmax 0.0103%, afr) (gnomAD).

What do computational predictors say about ESPN p.Arg19Lys (c.56G>A)?

AlphaMissense predicts likely benign (score 0.0781) — an in-silico prediction, not a clinical call.

ESPN p.Arg19Lys

c.56G>A · rs996170464 · VCV1311449

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0781 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0103%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0781	likely benign
REVEL	0.067	moderately benign-leaning
SaProt	LLR -8.96	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 0.2	GERP -2.7, phastCons 0.65
Regional constraint	o/e 0.88	unconstrained · MANE · 21 kb · p 0.002 · regional, not allelic
Overall
CADD	9.317	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 0.0103% African / African-American · 7/67,856 alleles

Filtering AF 0.00478% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00335%

Overall 0.000545% 8/1,468,372 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0103%	9,694
Admixed American	0.0024%	41,584

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.Arg19Lys
Coding: c.56G>A
MANE Select: NM_031475
dbSNP: rs996170464
Type: single nucleotide variant
Location: chr1:6425011 (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-arg19lys (accessed [today's date]).

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