Is ESPL1 p.Ser1422Phe (c.4265C>T) pathogenic?

ESPL1 p.Ser1422Phe (c.4265C>T) is classified Uncertain significance in ESPL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-25). AlphaMissense: likely benign (0.1342); Very rare (popmax 8.47e-05%, nfe).

How common is ESPL1 p.Ser1422Phe (c.4265C>T) in the general population?

ESPL1 p.Ser1422Phe (c.4265C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about ESPL1 p.Ser1422Phe (c.4265C>T)?

AlphaMissense predicts likely benign (score 0.1342) — an in-silico prediction, not a clinical call.

ESPL1 p.Ser1422Phe

c.4265C>T · VCV4019753

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1342 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1342	likely benign
REVEL	0.092	moderately benign-leaning
SaProt	LLR -9.56	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 1.1	GERP -0.53, phastCons 0.26
Regional constraint	o/e 0.84	unconstrained · MANE · 5,935 bp · p 7.9e-06 · regional, not allelic
Overall
CADD	21.5	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 8.47e-05% European (non-Finnish) · 1/1,180,030 alleles

Overall 6.84e-05% 1/1,461,302 alleles · very rare

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.Ser1422Phe
Coding: c.4265C>T
MANE Select: NM_012291
Type: single nucleotide variant
Location: chr12:53288060 (GRCh38)
Gene constraint: LOEUF 0.292 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 75.67 · 9 PDB
Residue 1422: the 'disordered' region

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-ser1422phe (accessed [today's date]).

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