Is ESPN p.Ser690Leu (c.2069C>T) pathogenic?

ESPN p.Ser690Leu (c.2069C>T) is classified Uncertain significance in ESPN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-12-14). AlphaMissense: likely benign (0.0796); Ultra-rare (popmax 0.0424%, eas); Associated with Usher syndrome, type 1M.

What condition is associated with ESPN p.Ser690Leu (c.2069C>T)?

ESPN p.Ser690Leu (c.2069C>T) is associated with Usher syndrome, type 1M, autosomal recessive nonsyndromic hearing loss 36 (ClinVar).

How common is ESPN p.Ser690Leu (c.2069C>T) in the general population?

ESPN p.Ser690Leu (c.2069C>T) is ultra-rare (popmax 0.0424%, eas) (gnomAD).

What do computational predictors say about ESPN p.Ser690Leu (c.2069C>T)?

AlphaMissense predicts likely benign (score 0.0796) — an in-silico prediction, not a clinical call.

ESPN p.Ser690Leu

c.2069C>T · rs117053591 · VCV1307782

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0796 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0424%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Usher syndrome, type 1M

Computational evidence

Protein change
AlphaMissense	0.0796	likely benign
REVEL	0.112	moderately benign-leaning
SaProt	LLR -7.95	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 1.2	GERP 0.2, phastCons 0.76
Regional constraint	o/e 0.98	unconstrained · MANE · 11 kb · p 0.7 · regional, not allelic
Overall
CADD	16.65	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 0.0424% East Asian · 19/44,824 alleles

Filtering AF 0.0277% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.023%

Overall 0.0018% 29/1,611,252 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0424%	2,359
South Asian	0.0011%	90,684
European (non-Finnish)	0.000763%	131,028

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.Ser690Leu
Coding: c.2069C>T
MANE Select: NM_031475
dbSNP: rs117053591
Type: single nucleotide variant
Location: chr1:6451840 (GRCh38)
Gene constraint: LOEUF 1.307 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.76
Residue 690: the 'disordered' region; a modified residue (phosphoserine)

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.Ser690= Benign/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
ESPN p.Ser312Leu 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-ser690leu (accessed [today's date]).

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