Is ESPL1 p.Arg1352Trp (c.4054C>T) pathogenic?

ESPL1 p.Arg1352Trp (c.4054C>T) is classified Uncertain significance in ESPL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-20). AlphaMissense: likely benign (0.1084); Ultra-rare (popmax 0.0164%, mid).

How common is ESPL1 p.Arg1352Trp (c.4054C>T) in the general population?

ESPL1 p.Arg1352Trp (c.4054C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about ESPL1 p.Arg1352Trp (c.4054C>T)?

AlphaMissense predicts likely benign (score 0.1084) — an in-silico prediction, not a clinical call.

ESPL1 p.Arg1352Trp

c.4054C>T · rs1312814330 · VCV3090463

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1084 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1084	likely benign
REVEL	0.054	moderately benign-leaning
SaProt	LLR -8.35	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 0.61	GERP -0.46, phastCons 0.001
Regional constraint	o/e 0.84	unconstrained · MANE · 5,935 bp · p 7.9e-06 · regional, not allelic
Overall
CADD	20.8	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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00164% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00142%

Overall 0.00198% 32/1,614,026 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
European (non-Finnish)	0.00237%	42,144
Remaining individualsnot grpmax-eligible	0.0016%	62,482
Finnishnot grpmax-eligible	0.00156%	63,976
African / African-American	0.00133%	74,936

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.Arg1352Trp
Coding: c.4054C>T
MANE Select: NM_012291
dbSNP: rs1312814330
Type: single nucleotide variant
Location: chr12:53286790 (GRCh38)
Gene constraint: LOEUF 0.292 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 75.67 · 9 PDB
Residue 1352: the 'disordered' region

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

Similar variants

ESPL1 p.Arg1352Gln Uncertain significance ★ ⚠ same residue
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

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-arg1352trp (accessed [today's date]).

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