Is A2M p.Ala615Val (c.1844C>T) pathogenic?

A2M p.Ala615Val (c.1844C>T) is classified Uncertain significance in A2M (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-03). AlphaMissense: likely benign (0.0998); Ultra-rare (popmax 0.0352%, mid).

How common is A2M p.Ala615Val (c.1844C>T) in the general population?

A2M p.Ala615Val (c.1844C>T) is ultra-rare (popmax 0.0352%, mid) (gnomAD).

What do computational predictors say about A2M p.Ala615Val (c.1844C>T)?

AlphaMissense predicts likely benign (score 0.0998) — an in-silico prediction, not a clinical call.

A2M p.Ala615Val

c.1844C>T · rs1017971143 · VCV3141194

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0998 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0352%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0998	likely benign
REVEL	0.103	moderately benign-leaning
SaProt	LLR -4.94	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.68	GERP 2.5
Regional constraint	o/e 0.84	unconstrained · MANE · 48 kb · p 4.5e-12 · regional, not allelic
Overall
CADD	16.78	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0352% Middle Eastern · 2/5,680 alleles

Filtering AF 0.00618% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00255%

Overall 0.00075% 12/1,600,796 alleles · ultra-rare exomes 12/1,448,556 · genomes 0/152,240 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0352%	2,840
East Asian	0.00225%	44,460
South Asian	0.00113%	88,392
European (non-Finnish)	0.000681%	146,750

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.Ala615Val
Coding: c.1844C>T
MANE Select: NM_000014
dbSNP: rs1017971143
Type: single nucleotide variant
Location: chr12:9098614 (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 p.Ala615= Likely benign ★ same residue
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

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-ala615val (accessed [today's date]).

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