Is A2ML1 p.Ala593fs (c.1777del) pathogenic?

A2ML1 p.Ala593fs (c.1777del) is classified Uncertain significance in A2ML1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-19). Very rare (popmax 0.00627%, nfe).

How common is A2ML1 p.Ala593fs (c.1777del) in the general population?

A2ML1 p.Ala593fs (c.1777del) is very rare (popmax 0.00627%, nfe) (gnomAD).

A2ML1 p.Ala593fs

c.1777del · rs758076462 · VCV1022051

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00627%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 15 of 36
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.8	GERP -1.4
Overall
CADD	23.5	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00627% European (non-Finnish) · 74/1,179,866 alleles

Filtering AF 0.00511% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00468%

Overall 0.00731% 118/1,613,586 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0562%	1,778
Remaining individualsnot grpmax-eligible	0.0112%	8,924
European (non-Finnish)grpmax	0.00627%	15,944
African / African-American	0.00134%	74,888

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: A2ML1
Protein: p.Ala593fs
Coding: c.1777del
MANE Select: NM_144670
dbSNP: rs758076462
Type: Deletion
Location: chr12:8847640 (GRCh38)
Gene constraint: LOEUF 0.953 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.61 · 5 PDB
Residue 593: a β-strand; a disulfide bond; a UniProt-annotated variant site (risk factor for otitis media)

Full A2ML1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

A2ML1 p.Ala593Glu Uncertain significance ★★ ⚠ same residue
A2ML1 p.Ala593= Likely benign ★★ same residue
A2ML1 p.Ala593Val Uncertain significance ★ ⚠ same residue
A2ML1 c.3718-2del Uncertain significance ★★ same type
A2ML1 c.2764+20del Likely benign ★★ same type
A2ML1 c.4061+11_4061+12del Benign/Likely benign ★★ same type
A2ML1 p.Ala1226fs Benign ★★ same type
A2ML1 p.Ser482fs 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/a2ml1-p-ala593fs (accessed [today's date]).

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