Is A2ML1 p.Phe301fs (c.900del) pathogenic?

A2ML1 p.Phe301fs (c.900del) is classified Uncertain significance in A2ML1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-15). Very rare (popmax 0.000254%, nfe).

How common is A2ML1 p.Phe301fs (c.900del) in the general population?

A2ML1 p.Phe301fs (c.900del) is very rare (popmax 0.000254%, nfe) (gnomAD).

A2ML1 p.Phe301fs

c.900del · VCV3649885

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 0.000254%, 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 9 of 36
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 2.9	GERP 0.14, phastCons 0.05

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000254% European (non-Finnish) · 3/1,179,830 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,461,468 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.Phe301fs
Coding: c.900del
MANE Select: NM_144670
Type: Deletion
Location: chr12:8838379 (GRCh38)
Gene constraint: LOEUF 0.953 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.61 · 5 PDB
Residue 301: 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.Phe301Ser 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
A2ML1 c.2234+2del Uncertain significance ★ same type
A2ML1 c.63-16_63-14del 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-phe301fs (accessed [today's date]).

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