Is A2ML1 p.Pro86fs (c.252_256dup) pathogenic?

A2ML1 p.Pro86fs (c.252256dup) is classified Uncertain significance in A2ML1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-30). Very rare (popmax 0.00017%, nfe).

How common is A2ML1 p.Pro86fs (c.252_256dup) in the general population?

A2ML1 p.Pro86fs (c.252_256dup) is very rare (popmax 0.00017%, nfe) (gnomAD).

A2ML1 p.Pro86fs

c.252_256dup · VCV3702591

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 0.00017%, 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 3 of 36
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 4.8	GERP 1.7, phastCons 0.96
Overall
CADD	32.0	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 0.00017% European (non-Finnish) · 2/1,179,676 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,613,282 alleles · very rare

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.Pro86fs
Coding: c.252_256dup
MANE Select: NM_144670
Type: Duplication
Location: chr12:8823723 (GRCh38)
Gene constraint: LOEUF 0.953 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.61 · 5 PDB
Residue 86: an α-helix

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

Similar variants

A2ML1 p.Pro86Leu Uncertain significance ★★ ⚠ same residue
A2ML1 p.Pro86Ser Uncertain significance ★★ ⚠ same residue
A2ML1 p.Asp631delinsValTer Uncertain significance ★★ same type
A2ML1 c.3108-3dup Benign ★★ same type
A2ML1 c.1249-19_1319dup Uncertain significance ★ same type
A2ML1 c.1684-47_1724dup Uncertain significance ★ same type
A2ML1 c.1834-20_1887dup Uncertain significance ★ same type
A2ML1 c.3718-16_3791dup 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/a2ml1-p-pro86fs (accessed [today's date]).

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