Is A2ML1 p.Phe715fs (c.2145del) pathogenic?

A2ML1 p.Phe715fs (c.2145del) is classified Conflicting classifications of pathogenicity in A2ML1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-01-14). Ultra-rare (popmax 0.0334%, nfe).

How common is A2ML1 p.Phe715fs (c.2145del) in the general population?

A2ML1 p.Phe715fs (c.2145del) is ultra-rare (popmax 0.0334%, nfe) (gnomAD).

A2ML1 p.Phe715fs

c.2145del · rs759217676 · VCV643431

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0334%, 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 18 of 36
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -3.6	GERP -0.7
Overall
CADD	17.53	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 0.0334% European (non-Finnish) · 394/1,179,370 alleles

Filtering AF 0.0306% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0295%

Overall 0.0257% 414/1,611,738 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0334%	2,993
Remaining individualsnot grpmax-eligible	0.0128%	7,804
Admixed American	0.00839%	11,912
African / African-American	0.00669%	14,953
Finnishnot grpmax-eligible	0.00315%	31,784

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.Phe715fs
Coding: c.2145del
MANE Select: NM_144670
dbSNP: rs759217676
Type: Deletion
Location: chr12:8850182 (GRCh38)
Gene constraint: LOEUF 0.953 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.61 · 5 PDB
Residue 715: a disulfide bond; the 'bait region' region; 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 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
A2ML1 p.Ala593fs 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-phe715fs (accessed [today's date]).

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