Is APEX2 p.Arg327Cys (c.979C>T) pathogenic?

APEX2 p.Arg327Cys (c.979C>T) is classified Uncertain significance in APEX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-04). AlphaMissense: likely benign (0.0764); Ultra-rare (popmax 0.0829%, eas).

How common is APEX2 p.Arg327Cys (c.979C>T) in the general population?

APEX2 p.Arg327Cys (c.979C>T) is ultra-rare (popmax 0.0829%, eas) (gnomAD).

What do computational predictors say about APEX2 p.Arg327Cys (c.979C>T)?

AlphaMissense predicts likely benign (score 0.0764) — an in-silico prediction, not a clinical call.

APEX2 p.Arg327Cys

c.979C>T · rs138407648 · VCV3127810

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0764 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0829%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0764	likely benign
REVEL	0.12	moderately benign-leaning
SaProt	LLR -11.07	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.7	GERP 1.4, phastCons 0.93
Regional constraint	o/e 0.82	unconstrained · MANE · 7,009 bp · p 0.00024 · regional, not allelic
Overall
CADD	18.27	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0829% East Asian · 28/33,769 alleles

Filtering AF 0.0589% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0508%

Overall 0.0335% 405/1,210,184 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0829%	1,206
Admixed American	0.0458%	2,183
European (non-Finnish)	0.036%	2,780
Remaining individualsnot grpmax-eligible	0.0357%	2,801
Finnishnot grpmax-eligible	0.0257%	3,887
African / African-American	0.00524%	19,076
Ashkenazi Jewishnot grpmax-eligible	0.00454%	22,035
South Asian	0.00176%	56,796

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.Arg327Cys
Coding: c.979C>T
MANE Select: NM_014481
dbSNP: rs138407648
Type: single nucleotide variant
Location: chrX:55006857 (GRCh38)
Structure: AlphaFold pLDDT 78.87

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

Similar variants

APEX2 p.Arg327His Uncertain significance ★ ⚠ same residue
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

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-arg327cys (accessed [today's date]).

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