Is ALYREF p.Leu16= (c.46C>T) pathogenic?

ALYREF p.Leu16= (c.46C>T) is classified Likely benign in ALYREF (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-03-11). Ultra-rare (popmax 0.0369%, amr); Associated with ALYREF-related disorder.

What condition is associated with ALYREF p.Leu16= (c.46C>T)?

ALYREF p.Leu16= (c.46C>T) is associated with ALYREF-related disorder (ClinVar).

How common is ALYREF p.Leu16= (c.46C>T) in the general population?

ALYREF p.Leu16= (c.46C>T) is ultra-rare (popmax 0.0369%, amr) (gnomAD).

ALYREF p.Leu16=

c.46C>T · VCV3350262

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0369%, amr)

Conditions

ALYREF-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP -1.1, phastCons 1
Overall
CADD	11.23	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0369% Admixed American · 15/40,674 alleles

Filtering AF 0.0226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0183%

Overall 0.00125% 16/1,283,626 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0369%	2,712
Remaining individualsnot grpmax-eligible	0.00185%	53,976

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: ALYREF
Protein: p.Leu16=
Coding: c.46C>T
MANE Select: NM_005782
Type: single nucleotide variant
Location: chr17:81891535 (GRCh38)
Gene constraint: LOEUF 0.235 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 65.65 · 4 PDB
Residue 16: the 'disordered' region; the 'rna-binding domain 1' region; the 'sufficient for rna-binding, interaction with nxf1-nxt1 heterodimer' region

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

Disease context

ALYREF-related disorder

Similar variants

ALYREF p.Pro2His Uncertain significance ★ same condition
ALYREF p.Arg231Leu Uncertain significance same condition
ALYREF p.Gln253Glu Uncertain significance ★ same type
ALYREF p.Ser4Phe Uncertain significance ★ same type
ALYREF p.Ser201= Likely benign ★ 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/alyref-p-leu16 (accessed [today's date]).

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