Is ASXL3 p.Pro718Ser (c.2152C>T) pathogenic?

ASXL3 p.Pro718Ser (c.2152C>T) is classified Conflicting classifications of pathogenicity in ASXL3 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-11-01). AlphaMissense: likely benign (0.1281); Very rare (popmax 0.00144%, nfe).

How common is ASXL3 p.Pro718Ser (c.2152C>T) in the general population?

ASXL3 p.Pro718Ser (c.2152C>T) is very rare (popmax 0.00144%, nfe) (gnomAD).

What do computational predictors say about ASXL3 p.Pro718Ser (c.2152C>T)?

AlphaMissense predicts likely benign (score 0.1281) — an in-silico prediction, not a clinical call.

ASXL3 p.Pro718Ser

c.2152C>T · rs905872208 · VCV385306

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1281 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00144%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1281	likely benign
REVEL	0.173	moderately benign-leaning
SaProt	LLR -7.51	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 7.6	GERP 2.6, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 7,973 bp · p 0.58 · regional, not allelic
Overall
CADD	23.0	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 0.00144% European (non-Finnish) · 17/1,179,898 alleles

Filtering AF 0.000878% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000718%

Overall 0.00105% 17/1,613,892 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: ASXL3
Protein: p.Pro718Ser
Coding: c.2152C>T
MANE Select: NM_030632
dbSNP: rs905872208
Type: single nucleotide variant
Location: chr18:33739556 (GRCh38)
Gene constraint: LOEUF 0.229 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 39.70
Residue 718: the 'disordered' region

Full ASXL3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ASXL3 p.Pro718= Uncertain significance ★ same residue
ASXL3 p.Pro718Leu Uncertain significance ★ ⚠ same residue
ASXL3 c.3039+1G>A Pathogenic ★★ same type
ASXL3 p.Arg1036Ter Pathogenic/Likely pathogenic ★★ same type
ASXL3 p.Arg1068Ter Pathogenic/Likely pathogenic ★★ same type
ASXL3 p.Arg1117Ter Pathogenic/Likely pathogenic ★★ same type
ASXL3 p.Arg1444Ter Pathogenic/Likely pathogenic ★★ same type
ASXL3 p.Arg1467Ter Pathogenic ★★ 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/asxl3-p-pro718ser (accessed [today's date]).

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