Is ADAM2 p.Cys336Arg (c.1006T>C) pathogenic?

ADAM2 p.Cys336Arg (c.1006T>C) is classified Uncertain significance in ADAM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-07). AlphaMissense: likely pathogenic (0.9926); Ultra-rare (popmax 0.0719%, sas).

How common is ADAM2 p.Cys336Arg (c.1006T>C) in the general population?

ADAM2 p.Cys336Arg (c.1006T>C) is ultra-rare (popmax 0.0719%, sas) (gnomAD).

What do computational predictors say about ADAM2 p.Cys336Arg (c.1006T>C)?

AlphaMissense predicts likely pathogenic (score 0.9926) — an in-silico prediction, not a clinical call.

ADAM2 p.Cys336Arg

c.1006T>C · VCV4637338

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9926 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0719%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9926	likely pathogenic · top 1% in ADAM2
REVEL	0.801	moderately pathogenic-leaning
SaProt	LLR -15.29	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
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

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0719% South Asian · 65/90,394 alleles

Filtering AF 0.0578% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0528%

Overall 0.00422% 67/1,588,256 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0719%	1,391
Remaining individualsnot grpmax-eligible	0.00325%	30,815

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.Cys336Arg
Coding: c.1006T>C
MANE Select: NM_001464
Type: single nucleotide variant
Location: chr8:39777047 (GRCh38)
Gene constraint: LOEUF 1.188 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.05
Residue 336: a disulfide bond; 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-cys336arg (accessed [today's date]).

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