Is ADAM2 p.Val550Ile (c.1648G>A) pathogenic?

ADAM2 p.Val550Ile (c.1648G>A) is classified Uncertain significance in ADAM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-06). AlphaMissense: likely benign (0.0774); Very rare (popmax 0.00542%, nfe).

How common is ADAM2 p.Val550Ile (c.1648G>A) in the general population?

ADAM2 p.Val550Ile (c.1648G>A) is very rare (popmax 0.00542%, nfe) (gnomAD).

What do computational predictors say about ADAM2 p.Val550Ile (c.1648G>A)?

AlphaMissense predicts likely benign (score 0.0774) — an in-silico prediction, not a clinical call.

ADAM2 p.Val550Ile

c.1648G>A · VCV4637342

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0774 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00542%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0774	likely benign
REVEL	0.017	moderately benign-leaning
SaProt	LLR -5.30	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 -6.8	GERP -3
Regional constraint	o/e 1.08	unconstrained · MANE · 93 kb · p 0.019 · regional, not allelic
Overall
CADD	0.002	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 0.00542% European (non-Finnish) · 62/1,142,970 alleles

Filtering AF 0.00432% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00392%

Overall 0.00414% 65/1,568,708 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00542%	18,435
African / African-American	0.00271%	36,866
Remaining individualsnot grpmax-eligible	0.00164%	60,956

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.Val550Ile
Coding: c.1648G>A
MANE Select: NM_001464
Type: single nucleotide variant
Location: chr8:39755877 (GRCh38)
Gene constraint: LOEUF 1.188 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.05

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

Similar variants

ADAM2 p.Val550Glu Uncertain significance ★ ⚠ same residue
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

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-val550ile (accessed [today's date]).

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