Is ESPN p.Tyr854Cys (c.2561A>G) pathogenic?

ESPN p.Tyr854Cys (c.2561A>G) is classified Uncertain significance in ESPN (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-10-11). AlphaMissense: likely benign (0.1227); Ultra-rare (popmax 0.0406%, mid).

How common is ESPN p.Tyr854Cys (c.2561A>G) in the general population?

ESPN p.Tyr854Cys (c.2561A>G) is ultra-rare (popmax 0.0406%, mid) (gnomAD).

What do computational predictors say about ESPN p.Tyr854Cys (c.2561A>G)?

AlphaMissense predicts likely benign (score 0.1227) — an in-silico prediction, not a clinical call.

ESPN p.Tyr854Cys

c.2561A>G · rs369745516 · VCV1442340

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1227 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0406%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1227	likely benign
REVEL	0.309	indeterminate
SaProt	LLR -7.17	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.1	GERP 1.1, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 11 kb · p 0.7 · regional, not allelic
Overall
CADD	24.7	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 0.0406% Middle Eastern · 2/4,924 alleles

Filtering AF 0.00716% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00298%

Overall 0.00155% 25/1,611,064 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0406%	2,462
Admixed American	0.00667%	14,997
Remaining individualsnot grpmax-eligible	0.00642%	15,580
African / African-American	0.00134%	74,828
European (non-Finnish)	0.00119%	84,245

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.Tyr854Cys
Coding: c.2561A>G
MANE Select: NM_031475
dbSNP: rs369745516
Type: single nucleotide variant
Location: chr1:6460142 (GRCh38)
Gene constraint: LOEUF 1.307 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.76
Residue 854: a UniProt-annotated variant site (in dfnb36)

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-tyr854cys (accessed [today's date]).

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