Is A2M p.Leu18Arg (c.53T>G) pathogenic?

A2M p.Leu18Arg (c.53T>G) is classified Likely benign in A2M (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-06-17). AlphaMissense: likely benign (0.2082); Rare (popmax 0.331%, nfe); Associated with A2M-related disorder.

What condition is associated with A2M p.Leu18Arg (c.53T>G)?

A2M p.Leu18Arg (c.53T>G) is associated with A2M-related disorder (ClinVar).

How common is A2M p.Leu18Arg (c.53T>G) in the general population?

A2M p.Leu18Arg (c.53T>G) is rare (popmax 0.331%, nfe) (gnomAD).

What do computational predictors say about A2M p.Leu18Arg (c.53T>G)?

AlphaMissense predicts likely benign (score 0.2082) — an in-silico prediction, not a clinical call.

A2M p.Leu18Arg

c.53T>G · rs201671036 · VCV3041387

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2082 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.331%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

A2M-related disorder

Computational evidence

Protein change
AlphaMissense	0.2082	likely benign
REVEL	0.263	benign-leaning
SaProt	LLR -10.02	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.7	GERP 3.4, phastCons 0.96
Regional constraint	o/e 0.84	unconstrained · MANE · 48 kb · p 4.5e-12 · regional, not allelic
Overall
CADD	23.8	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.331% European (non-Finnish) · 3,907/1,179,476 alleles

Filtering AF 0.323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.319%

Overall 0.261% 4,212/1,613,492 alleles · rare

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	0.877%	114
European (non-Finnish)grpmax	0.331%	302
Remaining individualsnot grpmax-eligible	0.186%	538
Admixed American	0.17%	588
African / African-American	0.0547%	1,830
Finnishnot grpmax-eligible	0.0422%	2,371
South Asian	0.011%	9,107
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,586

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Leu18Arg
Coding: c.53T>G
MANE Select: NM_000014
dbSNP: rs201671036
Type: single nucleotide variant
Location: chr12:9115797 (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

Disease context

A2M-related disorder

Similar variants

A2M p.Ala981Ser Uncertain significance ★ ⚠ same condition
A2M c.1495-10T>C Likely benign same condition
A2M c.2597-4T>A Benign same condition
A2M p.Ala844Val Benign same condition
A2M p.Arg586Gln Likely benign same condition
A2M p.Arg704His Benign same condition
A2M p.Asn938Asp Likely benign ⚠ same condition
A2M p.Cys972Tyr Benign 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/a2m-p-leu18arg (accessed [today's date]).

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