Is ASH2L p.Pro18Leu (c.53C>T) pathogenic?

ASH2L p.Pro18Leu (c.53C>T) is classified Uncertain significance in ASH2L (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-20). AlphaMissense: likely benign (0.0959); Rare (popmax 0.44%, eas).

How common is ASH2L p.Pro18Leu (c.53C>T) in the general population?

ASH2L p.Pro18Leu (c.53C>T) is rare (popmax 0.44%, eas) (gnomAD).

What do computational predictors say about ASH2L p.Pro18Leu (c.53C>T)?

AlphaMissense predicts likely benign (score 0.0959) — an in-silico prediction, not a clinical call.

ASH2L p.Pro18Leu

c.53C>T · VCV4154479

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0959 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.44%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0959	likely benign
REVEL	0.09	moderately benign-leaning
SaProt	LLR -8.50	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 2.8	GERP -1.8, phastCons 0.051
Regional constraint	o/e 1.26	unconstrained · MANE · 1,477 bp · p 0.0061 · regional, not allelic
Overall
CADD	20.3	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 0.44% East Asian · 194/44,074 alleles

Filtering AF 0.389% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.37%

Overall 0.0122% 196/1,600,442 alleles · rare exomes 176/1,448,080 · genomes 20/152,362 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.44%	227
Remaining individualsnot grpmax-eligible	0.00324%	30,863

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.Pro18Leu
Coding: c.53C>T
MANE Select: NM_004674
Type: single nucleotide variant
Location: chr8:38105603 (GRCh38)
Gene constraint: LOEUF 0.529 · pLI 0.88 (gnomAD)
Structure: AlphaFold pLDDT 77.27 · 32 PDB
Residue 18: the 'disordered' region

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

Similar variants

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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-pro18leu (accessed [today's date]).

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