Is ESPL1 p.Ser1769Ile (c.5306G>T) pathogenic?

ESPL1 p.Ser1769Ile (c.5306G>T) is classified Uncertain significance in ESPL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-26). AlphaMissense: likely benign (0.1559); Rare (popmax 0.132%, mid).

How common is ESPL1 p.Ser1769Ile (c.5306G>T) in the general population?

ESPL1 p.Ser1769Ile (c.5306G>T) is rare (popmax 0.132%, mid) (gnomAD).

What do computational predictors say about ESPL1 p.Ser1769Ile (c.5306G>T)?

AlphaMissense predicts likely benign (score 0.1559) — an in-silico prediction, not a clinical call.

ESPL1 p.Ser1769Ile

c.5306G>T · rs143994085 · VCV2283885

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1559 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.132%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1559	likely benign
REVEL	0.088	moderately benign-leaning
SaProt	LLR -8.11	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 1.5	GERP -2.9, phastCons 1
Regional constraint	o/e 0.57	unconstrained · MANE · 3,377 bp · p 6.2e-23 · regional, not allelic
Overall
CADD	21.1	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 0.132% Middle Eastern · 8/6,060 alleles

Filtering AF 0.0657% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0479%

Overall 0.0195% 314/1,613,478 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.132%	758
Admixed American	0.07%	1,429
Remaining individualsnot grpmax-eligible	0.0352%	2,841
European (non-Finnish)	0.0203%	4,937
African / African-American	0.004%	25,021

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.Ser1769Ile
Coding: c.5306G>T
MANE Select: NM_012291
dbSNP: rs143994085
Type: single nucleotide variant
Location: chr12:53290411 (GRCh38)
Gene constraint: LOEUF 0.292 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 75.67 · 9 PDB
Residue 1769: 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-ser1769ile (accessed [today's date]).

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