Is ADAM8 p.Asp378Val (c.1133A>T) pathogenic?

ADAM8 p.Asp378Val (c.1133A>T) is classified Uncertain significance in ADAM8 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-10). AlphaMissense: likely benign (0.1528); Absent from gnomAD v4.1.

How common is ADAM8 p.Asp378Val (c.1133A>T) in the general population?

ADAM8 p.Asp378Val (c.1133A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ADAM8 p.Asp378Val (c.1133A>T)?

AlphaMissense predicts likely benign (score 0.1528) — an in-silico prediction, not a clinical call.

ADAM8 p.Asp378Val

c.1133A>T · rs2493539183 · VCV2295097

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1528 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt

Computational evidence

Protein change
AlphaMissense	0.1528	likely benign
SaProt	LLR -8.38	tolerated
⇒ AlphaMissense and SaProt both call this tolerated.
Splicing
SpliceAI	Δ0.22	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 0.32	GERP -2.3, phastCons 0.001
Regional constraint	o/e 0.98	unconstrained · MANE · 14 kb · p 0.43 · regional, not allelic
Overall
CADD	19.42	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ADAM8
Protein: p.Asp378Val
Coding: c.1133A>T
MANE Select: NM_001109
dbSNP: rs2493539183
Type: single nucleotide variant
Location: chr10:133271679 (GRCh38)
Gene constraint: LOEUF 1.423 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.28 · 1 PDB
Residue 378: a disulfide bond; the peptidase m12b domain; an α-helix

Full ADAM8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADAM8 p.Ala118= Benign ★★ same type
ADAM8 p.Ala490Thr Benign ★★ same type
ADAM8 p.Arg36His Benign ★★ ⚠ same type
ADAM8 p.Arg433Cys Benign ★★ ⚠ same type
ADAM8 c.228-2A>G Uncertain significance ★ same type
ADAM8 p.Ala119Ser Uncertain significance ★ ⚠ same type
ADAM8 p.Ala119Thr Uncertain significance ★ ⚠ same type
ADAM8 p.Ala164Ser 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/adam8-p-asp378val (accessed [today's date]).

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