Is ADAM21 p.Val48Met (c.142G>A) pathogenic?

ADAM21 p.Val48Met (c.142G>A) is classified Uncertain significance in ADAM21 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-16). AlphaMissense: likely benign (0.1306); Ultra-rare (popmax 0.0496%, mid).

How common is ADAM21 p.Val48Met (c.142G>A) in the general population?

ADAM21 p.Val48Met (c.142G>A) is ultra-rare (popmax 0.0496%, mid) (gnomAD).

What do computational predictors say about ADAM21 p.Val48Met (c.142G>A)?

AlphaMissense predicts likely benign (score 0.1306) — an in-silico prediction, not a clinical call.

ADAM21 p.Val48Met

c.142G>A · VCV4004807

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1306 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0496%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1306	likely benign
REVEL	0.104	moderately benign-leaning
SaProt	LLR -9.21	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 0.31	GERP -1.1, phastCons 0.93
Regional constraint	o/e 0.86	unconstrained · MANE · 151 bp · p 0.27 · regional, not allelic
Overall
CADD	20.8	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 0.0496% Middle Eastern · 3/6,052 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00812%

Overall 0.00186% 30/1,613,872 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0496%	2,017
South Asian	0.0165%	6,067
Remaining individualsnot grpmax-eligible	0.0048%	20,832
African / African-American	0.00133%	75,028
European (non-Finnish)	0.000678%	147,486

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: ADAM21
Protein: p.Val48Met
Coding: c.142G>A
MANE Select: NM_003813
Type: single nucleotide variant
Location: chr14:70457641 (GRCh38)
Gene constraint: LOEUF 1.913 · pLI 0.14 (gnomAD)
Structure: AlphaFold pLDDT 83.17

Full ADAM21 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADAM21 p.Val48Glu Uncertain significance ★ ⚠ same residue
ADAM21 p.Ala432Asp Uncertain significance ★ ⚠ same type
ADAM21 p.Ala432Thr Uncertain significance ★ ⚠ same type
ADAM21 p.Ala500Ser Uncertain significance ★ ⚠ same type
ADAM21 p.Ala718Pro Uncertain significance ★ ⚠ same type
ADAM21 p.Arg182Cys Uncertain significance ★ ⚠ same type
ADAM21 p.Arg317Cys Uncertain significance ★ ⚠ same type
ADAM21 p.Arg408His 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/adam21-p-val48met (accessed [today's date]).

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