Is ESPN p.Ser362Trp (c.1085C>G) pathogenic?

ESPN p.Ser362Trp (c.1085C>G) is classified Uncertain significance in ESPN (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-15). AlphaMissense: ambiguous (0.3769); Very rare (popmax 0.000124%); Associated with Inborn genetic diseases.

What condition is associated with ESPN p.Ser362Trp (c.1085C>G)?

ESPN p.Ser362Trp (c.1085C>G) is associated with Inborn genetic diseases (ClinVar).

How common is ESPN p.Ser362Trp (c.1085C>G) in the general population?

ESPN p.Ser362Trp (c.1085C>G) is very rare (popmax 0.000124%) (gnomAD).

What do computational predictors say about ESPN p.Ser362Trp (c.1085C>G)?

AlphaMissense predicts ambiguous (score 0.3769) — an in-silico prediction, not a clinical call.

ESPN p.Ser362Trp

c.1085C>G · rs754724599 · VCV2484637

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3769 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000124%)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3769	ambiguous
REVEL	0.675	pathogenic-leaning
SaProt	LLR -9.88	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.70 · evaluated, not missing
Constraint at this position
Conservation	phyloP 6	GERP 1.2, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 21 kb · p 0.002 · regional, not allelic
Overall
CADD	25.7	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 0.000124%

Overall 0.000124% 2/1,614,240 alleles · very rare exomes 2/1,461,880 · genomes 0/152,360 · joint denominator

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.Ser362Trp
Coding: c.1085C>G
MANE Select: NM_031475
dbSNP: rs754724599
Type: single nucleotide variant
Location: chr1:6444575 (GRCh38)
Gene constraint: LOEUF 1.307 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.76
Residue 362: the 'disordered' region

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.Ser362Leu Uncertain significance ★★ ⚠ same residue
ESPN p.Ser362= Likely benign ★ same residue
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

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-ser362trp (accessed [today's date]).

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