Is ESPL1 p.Arg1786Ser (c.5358G>T) pathogenic?

ESPL1 p.Arg1786Ser (c.5358G>T) is classified Uncertain significance in ESPL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-10). AlphaMissense: likely pathogenic (0.6653); Ultra-rare (popmax 0.0307%, afr).

How common is ESPL1 p.Arg1786Ser (c.5358G>T) in the general population?

ESPL1 p.Arg1786Ser (c.5358G>T) is ultra-rare (popmax 0.0307%, afr) (gnomAD).

What do computational predictors say about ESPL1 p.Arg1786Ser (c.5358G>T)?

AlphaMissense predicts likely pathogenic (score 0.6653) — an in-silico prediction, not a clinical call.

ESPL1 p.Arg1786Ser

c.5358G>T · VCV4251065

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6653 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0307%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6653	likely pathogenic
REVEL	0.364	indeterminate
SaProt	LLR -9.05	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 0.86, phastCons 1
Regional constraint	o/e 0.57	unconstrained · MANE · 3,377 bp · p 6.2e-23 · regional, not allelic
Overall
CADD	23.9	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 0.0307% African / African-American · 23/74,920 alleles

Filtering AF 0.021% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0178%

Overall 0.00161% 26/1,612,442 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0307%	3,257
Remaining individualsnot grpmax-eligible	0.00481%	20,810

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: ESPL1
Protein: p.Arg1786Ser
Coding: c.5358G>T
MANE Select: NM_012291
Type: single nucleotide variant
Location: chr12:53290463 (GRCh38)
Gene constraint: LOEUF 0.292 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 75.67 · 9 PDB
Residue 1786: an α-helix

Full ESPL1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ESPL1 c.6162-10C>T Benign ★★ same type
ESPL1 p.Ala1462Thr Benign ★★ same type
ESPL1 p.Asn918Ser Benign ★★ same type
ESPL1 p.Gly1337Val Benign ★★ same type
ESPL1 p.Ile1488Asn Benign ★★ same type
ESPL1 p.Ser969= Benign ★★ same type
ESPL1 p.Thr2073Met Likely benign ★★ ⚠ same type
ESPL1 c.5241+1G>A Uncertain significance ★ same type

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/espl1-p-arg1786ser (accessed [today's date]).

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