Is ESPN p.Pro431fs (c.1287del) pathogenic?

ESPN p.Pro431fs (c.1287del) is classified Uncertain significance in ESPN (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-22). Ultra-rare (popmax 0.0232%, mid); Associated with Usher syndrome, type 1M.

What condition is associated with ESPN p.Pro431fs (c.1287del)?

ESPN p.Pro431fs (c.1287del) is associated with Usher syndrome, type 1M, autosomal recessive nonsyndromic hearing loss 36 (ClinVar).

How common is ESPN p.Pro431fs (c.1287del) in the general population?

ESPN p.Pro431fs (c.1287del) is ultra-rare (popmax 0.0232%, mid) (gnomAD).

ESPN p.Pro431fs

c.1287del · VCV3779629

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0232%, mid)

Conditions

Usher syndrome, type 1M

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 7 of 13
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1	GERP -1.5, phastCons 0.001
Overall
CADD	20.2	PHRED · no single calibrated threshold — expert panels disagree
Region caveats
Repeat context	seg dup	· reads may not map uniquely · confidence, not pathogenicity

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0232% Middle Eastern · 1/4,318 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00249%

Overall 0.00393% 54/1,375,478 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0232%	4,318
East Asian	0.00957%	10,454
Admixed American	0.00547%	18,277
European (non-Finnish)	0.00375%	26,635
Ashkenazi Jewishnot grpmax-eligible	0.00351%	28,520
Finnishnot grpmax-eligible	0.00338%	29,597
African / African-American	0.00139%	71,732

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.Pro431fs
Coding: c.1287del
MANE Select: NM_031475
Type: Deletion
Location: chr1:6445758 (GRCh38)
Gene constraint: LOEUF 1.307 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.76
Residue 431: the 'disordered' region

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

Disease context

Usher syndrome, type 1M — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal recessive nonsyndromic hearing loss 36

Similar variants

ESPN p.Pro431Ala Uncertain significance ★★ ⚠ same residue
ESPN p.Pro431= Likely benign ★★ same residue
ESPN p.Arg550fs Pathogenic ★ same condition
ESPN p.Arg790_Arg795del Pathogenic ★ same condition
ESPN p.Lys666fs Pathogenic ★ same condition
ESPN p.Ser694fs Pathogenic ★ same condition
ESPN p.Gly831_Tyr832insTer Pathogenic/Likely pathogenic same condition
ESPN p.Lys663fs Pathogenic 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-pro431fs (accessed [today's date]).

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