Is ADAM9 p.Pro406= (c.1218A>G) pathogenic?

ADAM9 p.Pro406= (c.1218A>G) is classified Benign in ADAM9 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-01). Common (popmax 11.8%, afr) — too common for a highly-penetrant pathogenic allele; Associated with cone-rod dystrophy 9.

What condition is associated with ADAM9 p.Pro406= (c.1218A>G)?

ADAM9 p.Pro406= (c.1218A>G) is associated with cone-rod dystrophy 9 (ClinVar).

How is Cone rod dystrophy inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

ADAM9 p.Pro406=

Q: How common is ADAM9 p.Pro406= (c.1218A>G) in the general population?

ADAM9 p.Pro406= (c.1218A>G) is common (popmax 11.8%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1218A>G · rs35438678 · VCV362931

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Common

common (popmax 11.8%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

cone-rod dystrophy 9

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 -0.038	GERP -3.4, phastCons 0.02
Overall
CADD	8.011	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 11.8% African / African-American · 8,845/75,018 alleles

Filtering AF 11.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 11.5%

Overall 0.625% 10,086/1,614,102 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	11.8%	8
Remaining individualsnot grpmax-eligible	0.878%	114
Admixed American	0.755%	133
Middle Eastern	0.594%	168
South Asian	0.0285%	3,503
European (non-Finnish)	0.015%	6,666

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: ADAM9
Protein: p.Pro406=
Coding: c.1218A>G
MANE Select: NM_003816
dbSNP: rs35438678
Type: single nucleotide variant
Location: chr8:39042033 (GRCh38)
Gene constraint: LOEUF 0.575 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 76.14
Residue 406: the peptidase m12b domain

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

Disease context

cone-rod dystrophy 9 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Cone rod dystrophy (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Adolescent, Adult, Childhood
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

ADAM9 p.Tyr213Ter Pathogenic/Likely pathogenic ★★ same condition
ADAM9 c.997-3C>G Uncertain significance ★★ same condition
ADAM9 p.Ala510Thr Uncertain significance ★★ same condition
ADAM9 p.Asn501Asp Uncertain significance ★★ ⚠ same condition
ADAM9 p.Asp132Tyr Uncertain significance ★★ ⚠ same condition
ADAM9 p.Asp362Gly Uncertain significance ★★ ⚠ same condition
ADAM9 p.Leu695Trp Uncertain significance ★★ ⚠ same condition
ADAM9 p.Met516Val 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-pro406 (accessed [today's date]).

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