Is ESPN p.Thr429Ile (c.1286C>T) pathogenic?

ESPN p.Thr429Ile (c.1286C>T) is classified Benign/Likely benign in ESPN (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-05-01). AlphaMissense: likely benign (0.0817); Rare (popmax 0.949%, mid); Associated with autosomal recessive nonsyndromic hearing loss 36.

What condition is associated with ESPN p.Thr429Ile (c.1286C>T)?

ESPN p.Thr429Ile (c.1286C>T) is associated with autosomal recessive nonsyndromic hearing loss 36, Usher syndrome, type 1M (ClinVar).

How common is ESPN p.Thr429Ile (c.1286C>T) in the general population?

ESPN p.Thr429Ile (c.1286C>T) is rare (popmax 0.949%, mid) (gnomAD).

What do computational predictors say about ESPN p.Thr429Ile (c.1286C>T)?

AlphaMissense predicts likely benign (score 0.0817) — an in-silico prediction, not a clinical call.

ESPN p.Thr429Ile

c.1286C>T · rs139266211 · VCV517052

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.0817 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.949%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal recessive nonsyndromic hearing loss 36

Computational evidence

Protein change
AlphaMissense	0.0817	likely benign
REVEL	0.092	moderately benign-leaning
SaProt	LLR -6.34	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 1	GERP -1.5, phastCons 0.001
Regional constraint	o/e 0.88	unconstrained · MANE · 21 kb · p 0.002 · regional, not allelic
Overall
CADD	9.071	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 0.949% Middle Eastern · 41/4,320 alleles

Filtering AF 0.719% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.638%

Overall 0.532% 8,104/1,524,410 alleles · rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	1.08%	93
Middle Easterngrpmax	0.949%	105
Ashkenazi Jewishnot grpmax-eligible	0.606%	165
Admixed American	0.591%	169
European (non-Finnish)	0.558%	179
Remaining individualsnot grpmax-eligible	0.548%	183
South Asian	0.334%	299
Amishnot grpmax-eligible	0.11%	906
African / African-American	0.0976%	1,025
East Asian	0.00478%	20,916

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Thr429Ile
Coding: c.1286C>T
MANE Select: NM_031475
dbSNP: rs139266211
Type: single nucleotide variant
Location: chr1:6445757 (GRCh38)
Gene constraint: LOEUF 1.307 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.76
Residue 429: the 'disordered' region

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

Disease context

autosomal recessive nonsyndromic hearing loss 36 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Usher syndrome, type 1M

Similar variants

ESPN p.Thr429Pro Uncertain significance ★ ⚠ same residue
ESPN p.Thr429= Likely benign same residue
ESPN c.1464+1G>A Likely pathogenic ★★ same condition
ESPN p.Ala624Thr Uncertain significance ★★ ⚠ same condition
ESPN p.Arg755Cys Uncertain significance ★★ ⚠ same condition
ESPN p.Asp744Asn Uncertain significance ★★ ⚠ same condition
ESPN p.Gly747Ser Uncertain significance ★★ ⚠ same condition
ESPN p.Lys476Gln Uncertain significance ★★ ⚠ 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-thr429ile (accessed [today's date]).

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