Is APEX2 p.Ser355Leu (c.1064C>T) pathogenic?

APEX2 p.Ser355Leu (c.1064C>T) is classified Uncertain significance in APEX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-10). AlphaMissense: likely benign (0.0759); Ultra-rare (popmax 0.0106%, sas).

How common is APEX2 p.Ser355Leu (c.1064C>T) in the general population?

APEX2 p.Ser355Leu (c.1064C>T) is ultra-rare (popmax 0.0106%, sas) (gnomAD).

What do computational predictors say about APEX2 p.Ser355Leu (c.1064C>T)?

AlphaMissense predicts likely benign (score 0.0759) — an in-silico prediction, not a clinical call.

APEX2 p.Ser355Leu

c.1064C>T · VCV3930969

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0759 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0106%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0759	likely benign
REVEL	0.03	moderately benign-leaning
SaProt	LLR -7.52	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 1.8	GERP 0.53, phastCons 0.82
Regional constraint	o/e 0.82	unconstrained · MANE · 7,009 bp · p 0.00024 · regional, not allelic
Overall
CADD	8.768	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 0.0106% South Asian · 6/56,810 alleles

Filtering AF 0.00459% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00308%

Overall 0.0024% 29/1,210,076 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0106%	9,468
Admixed American	0.00437%	22,899
Remaining individualsnot grpmax-eligible	0.0042%	23,801
Finnishnot grpmax-eligible	0.00215%	46,598
European (non-Finnish)	0.0019%	52,662
African / African-American	0.00175%	57,161

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: APEX2
Protein: p.Ser355Leu
Coding: c.1064C>T
MANE Select: NM_014481
Type: single nucleotide variant
Location: chrX:55006942 (GRCh38)
Structure: AlphaFold pLDDT 78.87
Residue 355: the 'disordered' region

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-ser355leu (accessed [today's date]).

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