Is APEX2 p.Glu448Val (c.1343A>T) pathogenic?

APEX2 p.Glu448Val (c.1343A>T) is classified Uncertain significance in APEX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-14). AlphaMissense: likely benign (0.1285); Absent from gnomAD v4.1.

How common is APEX2 p.Glu448Val (c.1343A>T) in the general population?

APEX2 p.Glu448Val (c.1343A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about APEX2 p.Glu448Val (c.1343A>T)?

AlphaMissense predicts likely benign (score 0.1285) — an in-silico prediction, not a clinical call.

APEX2 p.Glu448Val

c.1343A>T · VCV3931011

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1285 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1285	likely benign
REVEL	0.068	moderately benign-leaning
SaProt	LLR -7.40	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 6.1	GERP 1.4, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 7,009 bp · p 0.00024 · regional, not allelic
Overall
CADD	15.61	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: APEX2
Protein: p.Glu448Val
Coding: c.1343A>T
MANE Select: NM_014481
Type: single nucleotide variant
Location: chrX:55007221 (GRCh38)
Structure: AlphaFold pLDDT 78.87

Full APEX2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

APEX2 p.Ala309= Benign ★★ same type
APEX2 p.Ala83= Benign ★★ same type
APEX2 p.Arg141Cys Likely benign ★★ ⚠ same type
APEX2 p.Ala126Ser Uncertain significance ★ ⚠ same type
APEX2 p.Ala160Val Uncertain significance ★ ⚠ same type
APEX2 p.Ala267Thr Uncertain significance ★ ⚠ same type
APEX2 p.Ala29Ser Uncertain significance ★ ⚠ same type
APEX2 p.Ala372Gly 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/apex2-p-glu448val (accessed [today's date]).

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