Is ASH2L p.Pro537Ala (c.1609C>G) pathogenic?

ASH2L p.Pro537Ala (c.1609C>G) is classified Uncertain significance in ASH2L (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-11). AlphaMissense: likely benign (0.0535); Ultra-rare (popmax 0.0118%, amr).

How common is ASH2L p.Pro537Ala (c.1609C>G) in the general population?

ASH2L p.Pro537Ala (c.1609C>G) is ultra-rare (popmax 0.0118%, amr) (gnomAD).

What do computational predictors say about ASH2L p.Pro537Ala (c.1609C>G)?

AlphaMissense predicts likely benign (score 0.0535) — an in-silico prediction, not a clinical call.

ASH2L p.Pro537Ala

c.1609C>G · VCV3952569

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0535 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0118%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0535	likely benign
REVEL	0.279	benign-leaning
SaProt	LLR -8.61	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 1.7, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 5,558 bp · p 0.0018 · regional, not allelic
Overall
CADD	22.6	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 0.0118% Admixed American · 7/59,156 alleles

Filtering AF 0.0055% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00385%

Overall 0.000549% 8/1,456,882 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0118%	8,451
Remaining individualsnot grpmax-eligible	0.0016%	62,348

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: ASH2L
Protein: p.Pro537Ala
Coding: c.1609C>G
MANE Select: NM_004674
Type: single nucleotide variant
Location: chr8:38133535 (GRCh38)
Gene constraint: LOEUF 0.529 · pLI 0.88 (gnomAD)
Structure: AlphaFold pLDDT 77.27 · 32 PDB
Residue 537: the b30.2/spry domain; the 'interaction with rbbp5' region

Full ASH2L gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ASH2L p.Pro537Leu Uncertain significance ★ ⚠ same residue
ASH2L p.Ile576Val Likely pathogenic ★ ⚠ same type
ASH2L p.Ala14Thr Uncertain significance ★ ⚠ same type
ASH2L p.Ala2Thr Uncertain significance ★ ⚠ same type
ASH2L p.Ala314Thr Uncertain significance ★ ⚠ same type
ASH2L p.Ala375Thr Uncertain significance ★ ⚠ same type
ASH2L p.Ala412Thr Uncertain significance ★ ⚠ same type
ASH2L p.Ala435Thr 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/ash2l-p-pro537ala (accessed [today's date]).

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