Is ESPN p.Ser690= (c.2070G>A) pathogenic?

ESPN p.Ser690= (c.2070G>A) is classified Benign/Likely benign in ESPN (ClinVar, Multiple submitters, 9 submitters; last evaluated 2025-12-25). Rare (popmax 0.825%, mid); Associated with autosomal recessive nonsyndromic hearing loss 36.

What condition is associated with ESPN p.Ser690= (c.2070G>A)?

ESPN p.Ser690= (c.2070G>A) is associated with autosomal recessive nonsyndromic hearing loss 36, Usher syndrome, type 1M (ClinVar).

How common is ESPN p.Ser690= (c.2070G>A) in the general population?

ESPN p.Ser690= (c.2070G>A) is rare (popmax 0.825%, mid) (gnomAD).

ESPN p.Ser690=

c.2070G>A · rs142850918 · VCV226635

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

gnomAD v4.1

Rare

rare (popmax 0.825%, mid)

Conditions

autosomal recessive nonsyndromic hearing loss 36

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
REVEL	0.017	moderately benign-leaning
Splicing
SpliceAI	Δ0.38	acceptor gain · deltas
Constraint at this position
Conservation	phyloP -1.1	GERP -2.7
Overall
CADD	11.45	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.825% Middle Eastern · 49/5,940 alleles

Filtering AF 0.696% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.691%

Overall 0.606% 9,768/1,611,192 alleles · rare exomes 9,011/1,458,888 · genomes 757/152,304 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.825%	121
European (non-Finnish)	0.709%	141
Finnishnot grpmax-eligible	0.678%	148
Remaining individualsnot grpmax-eligible	0.553%	181
Ashkenazi Jewishnot grpmax-eligible	0.312%	321
Admixed American	0.267%	374
South Asian	0.253%	396
African / African-American	0.141%	708
East Asian	0.00446%	22,406

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.Ser690=
Coding: c.2070G>A
MANE Select: NM_031475
dbSNP: rs142850918
Type: single nucleotide variant
Location: chr1:6451841 (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

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.Ser690Leu Uncertain significance ★★ ⚠ 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-ser690 (accessed [today's date]).

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