Is ADAM2 p.Arg261Cys (c.781C>T) pathogenic?

ADAM2 p.Arg261Cys (c.781C>T) is classified Uncertain significance in ADAM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-25). AlphaMissense: likely pathogenic (0.8237); Ultra-rare (popmax 0.0667%, afr).

How common is ADAM2 p.Arg261Cys (c.781C>T) in the general population?

ADAM2 p.Arg261Cys (c.781C>T) is ultra-rare (popmax 0.0667%, afr) (gnomAD).

What do computational predictors say about ADAM2 p.Arg261Cys (c.781C>T)?

AlphaMissense predicts likely pathogenic (score 0.8237) — an in-silico prediction, not a clinical call.

ADAM2 p.Arg261Cys

c.781C>T · VCV4004558

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8237 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0667%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8237	likely pathogenic
REVEL	0.511	indeterminate
SaProt	LLR -9.31	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	Δ0.20	donor loss, 28 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 3.6	GERP 1.1, phastCons 0.95
Regional constraint	o/e 1.08	unconstrained · MANE · 93 kb · p 0.019 · regional, not allelic
Overall
CADD	25.1	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 0.0667% African / African-American · 48/71,918 alleles

Filtering AF 0.0517% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0463%

Overall 0.00649% 101/1,555,508 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0667%	1,498
Middle Eastern	0.017%	5,886
Remaining individualsnot grpmax-eligible	0.00668%	14,962
East Asian	0.00475%	21,056
European (non-Finnish)	0.00381%	26,228
Ashkenazi Jewishnot grpmax-eligible	0.00358%	27,934
South Asian	0.00125%	79,768

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.Arg261Cys
Coding: c.781C>T
MANE Select: NM_001464
Type: single nucleotide variant
Location: chr8:39788113 (GRCh38)
Gene constraint: LOEUF 1.188 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.05
Residue 261: 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-arg261cys (accessed [today's date]).

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