Is ADAM2 p.Met286Thr (c.857T>C) pathogenic?

ADAM2 p.Met286Thr (c.857T>C) is classified Uncertain significance in ADAM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-14). AlphaMissense: likely pathogenic (0.6752); Very rare (popmax 0.00228%, eas).

How common is ADAM2 p.Met286Thr (c.857T>C) in the general population?

ADAM2 p.Met286Thr (c.857T>C) is very rare (popmax 0.00228%, eas) (gnomAD).

What do computational predictors say about ADAM2 p.Met286Thr (c.857T>C)?

AlphaMissense predicts likely pathogenic (score 0.6752) — an in-silico prediction, not a clinical call.

ADAM2 p.Met286Thr

c.857T>C · VCV4637348

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6752 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00228%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6752	likely pathogenic
REVEL	0.406	indeterminate
SaProt	LLR -7.58	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	Δ0.21	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 93 kb · p 0.019 · regional, not allelic
Overall
CADD	24.1	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 0.00228% East Asian · 1/43,828 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000208% 3/1,441,604 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00228%	43,828
European (non-Finnish)	0.000171%	584,874

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: ADAM2
Protein: p.Met286Thr
Coding: c.857T>C
MANE Select: NM_001464
Type: single nucleotide variant
Location: chr8:39787008 (GRCh38)
Gene constraint: LOEUF 1.188 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.05
Residue 286: the peptidase m12b domain

Full ADAM2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADAM2 p.Ala238Val Uncertain significance ★ ⚠ same type
ADAM2 p.Ala266Gly Uncertain significance ★ ⚠ same type
ADAM2 p.Ala289Val Uncertain significance ★ ⚠ same type
ADAM2 p.Ala334Thr Uncertain significance ★ ⚠ same type
ADAM2 p.Ala463Val Uncertain significance ★ ⚠ same type
ADAM2 p.Ala668Val Uncertain significance ★ ⚠ same type
ADAM2 p.Arg161Gly Uncertain significance ★ ⚠ same type
ADAM2 p.Arg252Gly 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/adam2-p-met286thr (accessed [today's date]).

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