Is ESPL1 p.Thr433= (c.1299C>T) pathogenic?

ESPL1 p.Thr433= (c.1299C>T) is classified Likely benign in ESPL1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-09-18). Ultra-rare (popmax 0.036%, afr); Associated with ESPL1-related disorder.

What condition is associated with ESPL1 p.Thr433= (c.1299C>T)?

ESPL1 p.Thr433= (c.1299C>T) is associated with ESPL1-related disorder (ClinVar).

How common is ESPL1 p.Thr433= (c.1299C>T) in the general population?

ESPL1 p.Thr433= (c.1299C>T) is ultra-rare (popmax 0.036%, afr) (gnomAD).

ESPL1 p.Thr433=

c.1299C>T · rs149663100 · VCV3040825

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.036%, afr)

Conditions

ESPL1-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.28	GERP -2.6
Overall
CADD	9.649	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.036% African / African-American · 27/75,002 alleles

Filtering AF 0.0254% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0219%

Overall 0.00805% 130/1,614,048 alleles · ultra-rare exomes 113/1,461,854 · genomes 17/152,194 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.036%	2,778
Middle Eastern	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.0144%	6,946
European (non-Finnish)	0.00737%	13,563
Admixed American	0.00333%	29,993
Finnishnot grpmax-eligible	0.00312%	32,009
East Asian	0.00223%	44,882
South Asian	0.0011%	91,078

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.Thr433=
Coding: c.1299C>T
MANE Select: NM_012291
dbSNP: rs149663100
Type: single nucleotide variant
Location: chr12:53270728 (GRCh38)
Gene constraint: LOEUF 0.292 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 75.67 · 9 PDB
Residue 433: an α-helix

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

Disease context

ESPL1-related disorder

Similar variants

ESPL1 p.Thr433Ala Uncertain significance ★ ⚠ same residue
ESPL1 p.Ser1239Ter Uncertain significance ★ same condition
ESPL1 c.6161+7C>T Likely benign same condition
ESPL1 p.Ala116Val Benign same condition
ESPL1 p.Ala1438= Likely benign same condition
ESPL1 p.Arg1318Gln Likely benign same condition
ESPL1 p.Asn1723= Likely benign same condition
ESPL1 p.Asp1351= Likely benign 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/espl1-p-thr433 (accessed [today's date]).

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