Is ASH2L p.Pro580Ser (c.1738C>T) pathogenic?

ASH2L p.Pro580Ser (c.1738C>T) is classified Uncertain significance in ASH2L (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-28). AlphaMissense: likely pathogenic (0.6347); Absent from gnomAD v4.1.

How common is ASH2L p.Pro580Ser (c.1738C>T) in the general population?

ASH2L p.Pro580Ser (c.1738C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ASH2L p.Pro580Ser (c.1738C>T)?

AlphaMissense predicts likely pathogenic (score 0.6347) — an in-silico prediction, not a clinical call.

ASH2L p.Pro580Ser

c.1738C>T · rs2487035278 · VCV2367812

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6347 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6347	likely pathogenic
REVEL	0.718	pathogenic-leaning
SaProt	LLR -12.01	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.5, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 5,558 bp · p 0.0018 · regional, not allelic
Overall
CADD	27.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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: ASH2L
Protein: p.Pro580Ser
Coding: c.1738C>T
MANE Select: NM_004674
dbSNP: rs2487035278
Type: single nucleotide variant
Location: chr8:38138834 (GRCh38)
Gene constraint: LOEUF 0.529 · pLI 0.88 (gnomAD)
Structure: AlphaFold pLDDT 77.27 · 32 PDB
Residue 580: the b30.2/spry domain; the 'interaction with rbbp5' region; a β-strand

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

Similar variants

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
ASH2L p.Ala49Ser 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-pro580ser (accessed [today's date]).

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