Is ESPN p.Arg790Ser (c.2370G>C) pathogenic?

ESPN p.Arg790Ser (c.2370G>C) is classified Uncertain significance in ESPN (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-04). AlphaMissense: likely pathogenic (0.9651); Very rare (popmax 0.00666%, afr); Associated with Inborn genetic diseases.

What condition is associated with ESPN p.Arg790Ser (c.2370G>C)?

ESPN p.Arg790Ser (c.2370G>C) is associated with Inborn genetic diseases (ClinVar).

How common is ESPN p.Arg790Ser (c.2370G>C) in the general population?

ESPN p.Arg790Ser (c.2370G>C) is very rare (popmax 0.00666%, afr) (gnomAD).

What do computational predictors say about ESPN p.Arg790Ser (c.2370G>C)?

AlphaMissense predicts likely pathogenic (score 0.9651) — an in-silico prediction, not a clinical call.

ESPN p.Arg790Ser

c.2370G>C · VCV3510366

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9651 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00666%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9651	likely pathogenic · top 5% in ESPN
REVEL	0.549	indeterminate
SaProt	LLR -12.27	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.8	GERP 0.29, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 11 kb · p 0.7 · regional, not allelic
Overall
CADD	25.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00666% African / African-American · 5/75,062 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00161%

Overall 0.00031% 5/1,613,338 alleles · very rare

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.Arg790Ser
Coding: c.2370G>C
MANE Select: NM_031475
Type: single nucleotide variant
Location: chr1:6457228 (GRCh38)
Gene constraint: LOEUF 1.307 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.76
Residue 790: a UniProt-annotated variant site (in ush1m; results in impaired elongation of microvilli and stereocilia consistent with a loss of function in parallel actin filament bundle assembly; retains localization to microvilli and stereocilia)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ESPN p.Ala139Thr Uncertain significance ★★ ⚠ same condition
ESPN p.Ala23Thr Uncertain significance ★★ ⚠ same condition
ESPN p.Ala484Thr Uncertain significance ★★ ⚠ same condition
ESPN p.Ala729Glu Uncertain significance ★★ ⚠ same condition
ESPN p.Arg113His Uncertain significance ★★ ⚠ same condition
ESPN p.Arg335Cys Uncertain significance ★★ ⚠ same condition
ESPN p.Arg339Gln Uncertain significance ★★ ⚠ same condition
ESPN p.Arg478Cys 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-arg790ser (accessed [today's date]).

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