Is A2ML1 p.Ser482fs (c.1444_1445del) pathogenic?

A2ML1 p.Ser482fs (c.14441445del) is classified Benign in A2ML1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-01). Common (popmax 5.75%, afr) — too common for a highly-penetrant pathogenic allele.

A2ML1 p.Ser482fs

Q: How common is A2ML1 p.Ser482fs (c.1444_1445del) in the general population?

A2ML1 p.Ser482fs (c.1444_1445del) is common (popmax 5.75%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1444_1445del · rs143864957 · VCV241884

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Common

common (popmax 5.75%, afr) — too common for a highly-penetrant pathogenic allele

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 12 of 36
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -3.9	GERP -3.2
Overall
CADD	20.8	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 5.75% African / African-American · 4,316/75,006 alleles

Filtering AF 5.61% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.55%

Overall 0.299% 4,831/1,614,136 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	5.75%	17
Admixed American	0.345%	290
Remaining individualsnot grpmax-eligible	0.309%	324
Middle Eastern	0.182%	551
European (non-Finnish)	0.00839%	11,919
South Asian	0.00439%	22,772
Finnishnot grpmax-eligible	0.00156%	64,042

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.Ser482fs
Coding: c.1444_1445del
MANE Select: NM_144670
dbSNP: rs143864957
Type: Deletion
Location: chr12:8843329 (GRCh38)
Gene constraint: LOEUF 0.953 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.61 · 5 PDB
Residue 482: 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.Ser482Arg 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 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-ser482fs (accessed [today's date]).

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