Is A2ML1 p.Arg893Ter (c.2677C>T) pathogenic?

A2ML1 p.Arg893Ter (c.2677C>T) is classified Conflicting classifications of pathogenicity in A2ML1 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-04-27). Ultra-rare (popmax 0.0668%, mid); Associated with otitis media, susceptibility to.

What condition is associated with A2ML1 p.Arg893Ter (c.2677C>T)?

A2ML1 p.Arg893Ter (c.2677C>T) is associated with otitis media, susceptibility to (ClinVar).

How common is A2ML1 p.Arg893Ter (c.2677C>T) in the general population?

A2ML1 p.Arg893Ter (c.2677C>T) is ultra-rare (popmax 0.0668%, mid) (gnomAD).

A2ML1 p.Arg893Ter

c.2677C>T · rs199651558 · VCV217310

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0668%, mid)

Conditions

otitis media, susceptibility to

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 21 of 36
Splicing
SpliceAI	Δ0.23	donor loss · deltas
Pangolin	Δ0.39	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP -3.2	GERP -3.6
Overall
CADD	33.0	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 0.0668% Middle Eastern · 4/5,984 alleles

Filtering AF 0.0227% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0138%

Overall 0.0133% 214/1,608,412 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0668%	1,496
European (non-Finnish)	0.0161%	6,196
Remaining individualsnot grpmax-eligible	0.00963%	10,381
African / African-American	0.00801%	12,483
Admixed American	0.00672%	14,882
South Asian	0.00448%	22,330

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.Arg893Ter
Coding: c.2677C>T
MANE Select: NM_144670
dbSNP: rs199651558
Type: single nucleotide variant
Location: chr12:8854214 (GRCh38)
Gene constraint: LOEUF 0.953 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.61 · 5 PDB
Residue 893: a UniProt-annotated variant site (risk factor for otitis media)

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

Disease context

otitis media, susceptibility to — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

A2ML1 p.Arg893Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
A2ML1 p.Arg893Gly Uncertain significance ★ ⚠ same residue
A2ML1 p.Ala1445Glu Uncertain significance ★★ ⚠ same condition
A2ML1 p.Arg730Cys Uncertain significance ★★ ⚠ same condition
A2ML1 p.Arg730His Uncertain significance ★★ ⚠ same condition
A2ML1 p.Arg97Trp Uncertain significance ★★ ⚠ same condition
A2ML1 p.Asp640Asn Uncertain significance ★★ ⚠ same condition
A2ML1 p.Gln125His Uncertain significance ★★ ⚠ same condition

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-arg893ter (accessed [today's date]).

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