Is A2M p.Arg360Ter (c.1078C>T) pathogenic?

A2M p.Arg360Ter (c.1078C>T) is classified Uncertain significance in A2M (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-05). Very rare (popmax 0.00668%, afr).

How common is A2M p.Arg360Ter (c.1078C>T) in the general population?

A2M p.Arg360Ter (c.1078C>T) is very rare (popmax 0.00668%, afr) (gnomAD).

A2M p.Arg360Ter

c.1078C>T · VCV3339138

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00668%, afr)

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 10 of 36
Splicing
SpliceAI	Δ0.26	donor loss, 26 bp away · masked 0 · deltas
Pangolin	Δ0.27	loss · gain 0.01 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 2.9	GERP 1.6, phastCons 1
Overall
CADD	36.0	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 0.00668% African / African-American · 5/74,860 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00162%

Overall 0.00242% 39/1,612,266 alleles · very rare exomes 34/1,460,128 · genomes 5/152,138 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00668%	14,972
Finnishnot grpmax-eligible	0.00312%	32,005
European (non-Finnish)	0.00246%	40,639
Admixed American	0.00167%	59,996
Remaining individualsnot grpmax-eligible	0.0016%	62,416
South Asian	0.0011%	91,026

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: A2M
Protein: p.Arg360Ter
Coding: c.1078C>T
MANE Select: NM_000014
Type: single nucleotide variant
Location: chr12:9106262 (GRCh38)
Gene constraint: LOEUF 0.765 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.61 · 13 PDB

Full A2M gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

A2M c.3756+4G>A Benign/Likely benign ★★ same type
A2M p.Ala844= Benign ★★ same type
A2M p.Asp277Asn Benign ★★ same type
A2M p.Ile1000Val Benign ★★ same type
A2M p.Pro261Leu Benign ★★ same type
A2M p.Tyr1152= Benign/Likely benign ★★ same type
A2M p.Val120= Likely benign ★★ same type
A2M p.Val129= Benign ★★ 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/a2m-p-arg360ter (accessed [today's date]).

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