Is ESPN p.Ser719Arg (c.2155A>C) pathogenic?

ESPN p.Ser719Arg (c.2155A>C) is classified Likely pathogenic in ESPN (ClinVar, Single submitter, 2 submitters; last evaluated 2021-11-07). AlphaMissense: ambiguous (0.5005); Ultra-rare (popmax 0.0167%, mid); Associated with ESPN-related disorder.

What condition is associated with ESPN p.Ser719Arg (c.2155A>C)?

ESPN p.Ser719Arg (c.2155A>C) is associated with ESPN-related disorder, autosomal dominant nonsyndromic hearing loss 91 (ClinVar).

How common is ESPN p.Ser719Arg (c.2155A>C) in the general population?

ESPN p.Ser719Arg (c.2155A>C) is ultra-rare (popmax 0.0167%, mid) (gnomAD).

What do computational predictors say about ESPN p.Ser719Arg (c.2155A>C)?

AlphaMissense predicts ambiguous (score 0.5005) — an in-silico prediction, not a clinical call.

ESPN p.Ser719Arg

c.2155A>C · rs121908134 · VCV4420

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5005 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, mid)

Conditions

ESPN-related disorder

Computational evidence

Protein change
AlphaMissense	0.5005	ambiguous
REVEL	0.553	indeterminate
SaProt	LLR -7.95	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.3, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 11 kb · p 0.7 · regional, not allelic
Overall
CADD	22.2	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 0.0167% Middle Eastern · 1/5,996 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000548% 8/1,458,666 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0167%	5,996
European (non-Finnish)	0.000594%	168,412

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.Ser719Arg
Coding: c.2155A>C
MANE Select: NM_031475
dbSNP: rs121908134
Type: single nucleotide variant
Location: chr1:6451926 (GRCh38)
Gene constraint: LOEUF 1.307 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.76
Residue 719: a UniProt-annotated variant site (in dfnb36; irregular microvillar organization)

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

Disease context

ESPN-related disorder

Also linked: autosomal dominant nonsyndromic hearing loss 91

Similar variants

ESPN p.Asp744Asn Uncertain significance ★★ ⚠ same condition
ESPN c.1464+1G>T Likely pathogenic ★ same condition
ESPN c.2062-1G>T Likely pathogenic ★ same condition
ESPN c.991-2A>G Likely pathogenic ★ same condition
ESPN p.Gln447Ter Likely pathogenic ★ same condition
ESPN p.Arg774Gln Pathogenic ⚠ same condition
ESPN c.*4C>T Likely benign same condition
ESPN p.Arg791= Likely benign same condition

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-ser719arg (accessed [today's date]).

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