Is ADAM9 p.Pro754Arg (c.2261C>G) pathogenic?

ADAM9 p.Pro754Arg (c.2261C>G) is classified Uncertain significance in ADAM9 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-04). AlphaMissense: likely benign (0.0869); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with ADAM9 p.Pro754Arg (c.2261C>G)?

ADAM9 p.Pro754Arg (c.2261C>G) is associated with Inborn genetic diseases (ClinVar).

How common is ADAM9 p.Pro754Arg (c.2261C>G) in the general population?

ADAM9 p.Pro754Arg (c.2261C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ADAM9 p.Pro754Arg (c.2261C>G)?

AlphaMissense predicts likely benign (score 0.0869) — an in-silico prediction, not a clinical call.

ADAM9 p.Pro754Arg

c.2261C>G · rs2536393491 · VCV3146293

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0869 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0869	likely benign
REVEL	0.066	moderately benign-leaning
SaProt	LLR -7.05	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 5.2	GERP 2.5, phastCons 0.83
Regional constraint	o/e 1.01	unconstrained · MANE · 26 kb · p 0.88 · regional, not allelic
Overall
CADD	21.1	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: ADAM9
Protein: p.Pro754Arg
Coding: c.2261C>G
MANE Select: NM_003816
dbSNP: rs2536393491
Type: single nucleotide variant
Location: chr8:39091309 (GRCh38)
Gene constraint: LOEUF 0.575 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 76.14
Residue 754: the 'disordered' region

Full ADAM9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ADAM9 p.Ala145Glu Uncertain significance ★★ ⚠ same condition
ADAM9 p.Ala424Thr Uncertain significance ★★ ⚠ same condition
ADAM9 p.Ala534Pro Uncertain significance ★★ ⚠ same condition
ADAM9 p.Arg117Trp Uncertain significance ★★ ⚠ same condition
ADAM9 p.Arg164Gln Uncertain significance ★★ ⚠ same condition
ADAM9 p.Arg296Trp Uncertain significance ★★ ⚠ same condition
ADAM9 p.Arg596Gln Uncertain significance ★★ ⚠ same condition
ADAM9 p.Arg772Lys Uncertain significance ★★ ⚠ same condition

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/adam9-p-pro754arg (accessed [today's date]).

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