Is SAMD9 p.Arg685Ter (c.2053C>T) pathogenic?

SAMD9 p.Arg685Ter (c.2053C>T) is classified Uncertain significance in SAMD9 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-12-16). Ultra-rare (popmax 0.03%, amr); Associated with MIRAGE syndrome.

What condition is associated with SAMD9 p.Arg685Ter (c.2053C>T)?

SAMD9 p.Arg685Ter (c.2053C>T) is associated with MIRAGE syndrome (ClinVar).

How common is SAMD9 p.Arg685Ter (c.2053C>T) in the general population?

SAMD9 p.Arg685Ter (c.2053C>T) is ultra-rare (popmax 0.03%, amr) (gnomAD).

How is MIRAGE syndrome inherited?

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

SAMD9 p.Arg685Ter

c.2053C>T · rs763070754 · VCV1043583

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.03%, amr)

Conditions

MIRAGE syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (3 of 3) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.95	phastCons 0.33
Overall
CADD	35.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.03% Admixed American · 18/59,994 alleles

Filtering AF 0.0194% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.016%

Overall 0.00229% 37/1,613,814 alleles · ultra-rare exomes 29/1,461,724 · genomes 8/152,090 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.03%	3,333
Remaining individualsnot grpmax-eligible	0.008%	12,496
African / African-American	0.00267%	37,451
South Asian	0.0011%	91,080
European (non-Finnish)	0.000932%	107,261

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: SAMD9
Protein: p.Arg685Ter
Coding: c.2053C>T
MANE Select: NM_017654
dbSNP: rs763070754
Type: single nucleotide variant
Location: chr7:93104045 (GRCh38)
Gene constraint: LOEUF 1.773 · pLI 0.03 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 83.79 · 10 PDB

Full SAMD9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

MIRAGE syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For MIRAGE syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Antenatal, Neonatal

Similar variants

SAMD9 p.Arg685Gln Pathogenic/Likely pathogenic ★★ ⚠ same residue
SAMD9 p.Arg685= Likely benign ★ same residue
SAMD9 p.Arg1293Trp Pathogenic ★★ ⚠ same condition
SAMD9 p.Arg459Gln Pathogenic ★★ ⚠ same condition
SAMD9 p.Arg824Gln Pathogenic ★★ ⚠ same condition
SAMD9 p.Arg982Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
SAMD9 p.Arg982His Pathogenic/Likely pathogenic ★★ ⚠ same condition
SAMD9 p.Arg1334Ile 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/samd9-p-arg685ter (accessed [today's date]).

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