Is ADAM8 p.Val754= (c.2262C>T) pathogenic?

ADAM8 p.Val754= (c.2262C>T) is classified Likely benign in ADAM8 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-19). Very rare (popmax 0.00169%, amr).

How common is ADAM8 p.Val754= (c.2262C>T) in the general population?

ADAM8 p.Val754= (c.2262C>T) is very rare (popmax 0.00169%, amr) (gnomAD).

ADAM8 p.Val754=

c.2262C>T · rs1393810404 · VCV3146131

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00169%, amr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -6.9	GERP -2.1
Overall
CADD	0.136	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00169% Admixed American · 1/59,328 alleles

Overall 0.000124% 2/1,609,394 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00169%	59,328
European (non-Finnish)	8.48e-05%	1,178,894

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: ADAM8
Protein: p.Val754=
Coding: c.2262C>T
MANE Select: NM_001109
dbSNP: rs1393810404
Type: single nucleotide variant
Location: chr10:133267409 (GRCh38)
Gene constraint: LOEUF 1.423 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.28 · 1 PDB
Residue 754: the 'disordered' region

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-val754 (accessed [today's date]).

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