Is ASH2L p.Pro493Ser (c.1477C>T) pathogenic?

ASH2L p.Pro493Ser (c.1477C>T) is classified Uncertain significance in ASH2L (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-05). AlphaMissense: likely benign (0.3253); Ultra-rare (popmax 0.0165%, mid).

How common is ASH2L p.Pro493Ser (c.1477C>T) in the general population?

ASH2L p.Pro493Ser (c.1477C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about ASH2L p.Pro493Ser (c.1477C>T)?

AlphaMissense predicts likely benign (score 0.3253) — an in-silico prediction, not a clinical call.

ASH2L p.Pro493Ser

c.1477C>T · VCV3436159

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3253 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3253	likely benign
REVEL	0.716	pathogenic-leaning
SaProt	LLR -11.78	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.1, phastCons 1
Regional constraint	o/e 0.60	unconstrained · MANE · 26 kb · p 8.6e-20 · regional, not allelic
Overall
CADD	27.5	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 0.0165% Middle Eastern · 1/6,076 alleles

Filtering AF 0.00153% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0013%

Overall 0.0018% 29/1,613,842 alleles · ultra-rare exomes 27/1,461,712 · genomes 2/152,130 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,076
European (non-Finnish)	0.0022%	45,383
Remaining individualsnot grpmax-eligible	0.0016%	62,470
African / African-American	0.00134%	74,882

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.Pro493Ser
Coding: c.1477C>T
MANE Select: NM_004674
Type: single nucleotide variant
Location: chr8:38128901 (GRCh38)
Gene constraint: LOEUF 0.529 · pLI 0.88 (gnomAD)
Structure: AlphaFold pLDDT 77.27 · 32 PDB
Residue 493: 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.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-pro493ser (accessed [today's date]).

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